Compositions, methods &amp; systems for respiratory delivery of two or more active agents

ABSTRACT

Compositions, methods and systems are provided for pulmonary or nasal delivery of two or more active agents via a metered dose inhaler. In one embodiment, the compositions include a suspension medium, active agent particles, and suspending particles, in which the active agent particles and suspending particles form a co-suspension within the suspension medium.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.12/790,710, filed on May 28, 2010; which claims the benefit of U.S.Provisional Application No. 61/182,565, filed May 29, 2009; U.S.Provisional Application No. 61/258,172, filed Nov. 4, 2009; U.S.Provisional Application No. 61/309,365, filed Mar. 1, 2010; and U.S.Provisional Application No. 61/345,536 filed May 17, 2010. Thisapplication hereby incorporates by reference the U.S. priorityapplications enumerated herein.

TECHNICAL FIELD

The present disclosure relates generally to compositions, methods andsystems for respiratory delivery of two or more active agents. Incertain embodiments, the present disclosure relates to compositions,methods, and systems for respiratory delivery of two or more activeagents, wherein at least one of the active agents is selected fromlong-acting muscarinic antagonist (“LAMA”), long-acting β₂ adrenergicagonist (“LABA”), and corticosteroid active agents.

BACKGROUND

Methods of targeted drug delivery that deliver an active agent at thesite of action are often desirable. For example, targeted delivery ofactive agents can reduce undesirable side effects, lower dosingrequirements and decrease therapeutic costs. In the context ofrespiratory delivery, inhalers are well known devices for administeringan active agent to a subject's respiratory tract, and several differentinhaler systems are currently commercially available. Three commoninhaler systems include dry powder inhalers, nebulizers and metered doseinhalers (MDIs).

MDIs may be used to deliver medicaments in a solubilized form or as asuspension. Typically, MDIs use a relatively high vapor pressurepropellant to expel aerosolized droplets containing an active agent intothe respiratory tract when the MDI is activated. Dry powder inhalersgenerally rely on the patient's inspiratory efforts to introduce amedicament in a dry powder form to the respiratory tract. On the otherhand, nebulizers form a medicament aerosol to be inhaled by impartingenergy to a liquid solution or suspension.

MDIs are active delivery devices that utilize the pressure generated bya propellant. Conventionally, chlorofluorocarbons (CFCs) have been usedas propellants in MDI systems because of their low toxicity, desirablevapor pressure and suitability for formulation of stable suspensions.However, traditional CFC propellants are understood to have a negativeenvironmental impact, which has led to the development of alternativepropellants that are believed to be more environmentally-friendly, suchas perfluorinated compounds (PFCs) and hydrofluoroalkanes (HFAs).

The active agent to be delivered by a suspension MDI is typicallyprovided as a fine particulate dispersed within a propellant orcombination of two or more propellants (i.e., a propellant “system”). Inorder to form the fine particulates, the active agent is typicallymicronized. Fine particles of active agent suspended in a propellant orpropellant system tend to aggregate or flocculate rapidly. This isparticularly true of active agents present in micronized form. In turn,aggregation or flocculation of these fine particles may complicate thedelivery of the active agent. For example, aggregation or flocculationcan lead to mechanical failures, such as those that might be caused byobstruction of the valve orifice of the aerosol container. Unwantedaggregation or flocculation of drug particles may also lead to rapidsedimentation or creaming of drug particles, and such behavior mayresult in inconsistent dose delivery, which can be particularlytroublesome with highly potent, low dose medicaments. Another problemassociated with such suspension MDI formulations relates to crystalgrowth of the drug during storage, resulting in a decrease over time ofaerosol properties and delivered dose uniformity of such MDIs. Morerecently, solution approaches, such as those disclosed in U.S. Pat. No.6,964,759, have been proposed for MDI formulations containinganticholinergics.

One approach to improve aerosol performance in dry powder inhalers hasbeen to incorporate fine particle carrier particles, such as lactose.Use of such fine excipients has not been investigated to any greatextent for MDIs. A recent report by Young et al., “The influence ofmicronized particulates on the aerosolization properties of pressurizedmetered dose inhalers”; Aerosol Science 40, pgs. 324-337 (2009),suggests that the use of such fine particle carriers in MDIs actuallyresult in a decrease in aerosol performance.

In traditional CFC systems, when the active agent present in an MDIformulation is suspended in the propellant or propellant system,surfactants are often used to coat the surfaces of the active agent inorder to minimize or prevent the problem of aggregation and maintain asubstantially uniform dispersion. The use of surfactants in this manneris sometimes referred to as “stabilizing” the suspension. However, manysurfactants that are soluble and thus effective in CFC systems are noteffective in HFA and PFC propellant systems because such surfactantsexhibit different solubility characteristics in non-CFC propellants.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph, which depicts the delivered dose uniformity of aco-suspension formulation containing glycopyrrolate and formoterolfumarate prepared according to the present description.

FIG. 2 is a graph, which depicts the delivered dose ratio of theco-suspension formulation of FIG. 1.

FIG. 3 is a graph, which depicts the delivered dose uniformity of asecond co-suspension formulation prepared according to the presentdescription.

FIG. 4 is a graph, which depicts the delivered dose ratio of the secondco-suspension formulation of FIG. 3.

FIG. 5 is a graph, which depicts the delivered dose uniformity ofglycopyrrolate and formoterol fumarate in a co-suspension formulationprepared according to the present description upon storage underdifferent conditions as indicated.

FIG. 6 is a graph, which depicts the particle size distributions ofexemplary co-suspension formulations prepared according to the presentdescription upon storage under different conditions, as indicated.

FIG. 7 provides graphs illustrating the particle size distributionsachieved by an exemplary co-suspension including a combination ofglycopyrrolate and formoterol fumarate, upon storage at indicatedconditions.

FIG. 8 provides graphs illustrating the particle size distributionachieved by an exemplary co-suspension including a combination ofglycopyrrolate and formoterol fumarate compared to particle sizedistributions achieved by formulations including either glycopyrrolateor formoterol fumarate alone.

FIG. 9 is a graph, which depicts the serum glycopyrrolate and formoterolconcentration levels over time achieved after delivery of an exemplaryco-suspension including glycopyrrolate and formoterol fumarate preparedaccording to the present description. The serum concentration timeprofile of glycopyrrolate and formoterol fumarate delivered from theexemplary combination formulation is compared to that achieved bycompositions containing and delivering glycopyrrolate or formoterolfumarate alone.

FIG. 10 is a graph that depicts the formoterol particle sizedistribution achieved by a dual co-suspension prepared according to thepresent description, which included microcrystalline formoterol fumarateand glycopyrrolate active agent particles compared to a co-suspensiononly containing crystalline formoterol fumarate.

FIG. 11 is a graph that depicts the glycopyrrolate particle sizedistribution achieved by a dual co-suspension prepared according to thepresent description, which included microcrystalline glycopyrrolateactive agent particles and microcrystalline formoterol fumarate activeagent particles with two different particle size distributions (denoted“fine” and “coarse”) or spray dried formoterol fumarate.

FIG. 12 is a graph that depicts the formoterol fumarate particle sizedistribution achieved by a second dual co-suspension prepared accordingto the present description, which included microcrystalline formoterolfumarate and microcrystalline glycopyrrolate active agent particlescompared to one that contained microcrystalline glycopyrrolate activeagent particles and spray dried formoterol fumarate particles.

FIG. 13 is a graph, which depicts the delivered dose uniformity ofglycopyrrolate and formoterol fumarate in an exemplary dualco-suspension formulation prepared according to the present description.

FIG. 14 depicts the delivered dose uniformity for each active agentincluded in an exemplary triple co-suspension composition, whichincluded microcrystalline glycopyrrolate, formoterol fumarate andmometasone furoate active agent particles.

FIG. 15 is a graph depicting the formoterol fumarate aerodynamicparticle size distributions achieved in a triple co-suspension preparedaccording to the present description, which included microcrystallineglycopyrrolate, formoterol fumarate and mometasone furoate active agentparticles, compared to that achieved in a dual co-suspension whichincluded glycopyrrolate and formoterol fumarate.

FIG. 16 is a graph depicting the glycopyrrolate aerodynamic particlesize distributions achieved in a triple co-suspension prepared accordingto the present description, which included microcrystallineglycopyrrolate, formoterol fumarate and mometasone furoate active agentparticles, compared to that achieved in a dual co-suspension whichincluded glycopyrrolate and formoterol fumarate.

FIG. 17 is a graph depicting the glycopyrrolate and tiotropium bromideaerodynamic particle size distributions achieved by a tripleco-suspension prepared according to the present description, which, inaddition to either glycopyrrolate or tiotropium bromide active agentparticles, included formoterol fumarate and mometasone furoatemicrocrystalline active agent particles.

FIG. 18 is a graph depicting the glycopyrrolate aerodynamic sizedistribution achieved by a two dual and one single componentco-suspension prepared according to the present description. The doseproportionality between the two dual co-suspensions as well as theequivalency between the dual and the single component co-suspension isdisplayed.

FIG. 19 is a graph depicting the formoterol fumarate aerodynamic sizedistribution achieved by a two dual and two single componentco-suspensions prepared according to the present description. The doseproportionality between the two dual and two single componentco-suspensions as well as the equivalency between the dual and thesingle component co-suspension is displayed.

FIG. 20 is a graph depicting the dose delivered uniformity of ultra lowformoterol fumarate single component co-suspensions prepared accordingto the present description.

FIG. 21 is a graph depicting the cumulative response over time on thefirst day of administration of two treatments using combinationco-suspension compositions as described herein (GP/FF 72/9.6 and GP/FF36/9.6) compared to two different delivering a single active agent (onedelivering only glycopyrrolate—GP 36, and a second delivering onlytiotropium bromide—Spiriva). These compositions were administered topatients as part of the clinical study described in Example 12.Specifically, the graph illustrates the percent of patients achieving≥12% improvement in FEV₁ and the time at which such percentages wereachieved.

FIG. 22 is a graph illustrating the mean change from baseline in FEV₁AUC₀₋₁₂ on treatment day 7 (Day 7) for various study compositionsadministered to patients as part of the clinical study described inExample 12. Two treatments using combination co-suspension compositionsas described herein (GP/FF 72/9.6 and GP/FF 36/9.6) are compared to aplacebo and active compositions delivering a single active agent (onedelivering only glycopyrrolate—GP 36, and a second delivering onlytiotropium bromide—Spiriva.

FIG. 23 is a graph illustrating the mean change from baseline in FEV₁AUC₀₋₁₂ on treatment day 7 (Day 7) for various study compositionsadministered to patients as part of the clinical study described inExample 12. Two treatments using combination co-suspension compositionsas described herein (GP/FF 72/9.6 and GP/FF 36/9.6) are compared to aplacebo and various different active compositions delivering a singleactive agent (one delivering only glycopyrrolate—GP 36, and threedelivering only formoterol fumarate—FF 7.2, FF 9.6, and Foradil).

FIG. 24 is a graph illustrating the mean change from baseline in FEV₁AUC₀₋₁₂ on treatment day 7 (Day 7) for various study compositionsadministered to patients as part of the clinical study described inExample 12. Two treatments using combination co-suspension compositionsas described herein (GP/FF 72/9.6 and GP/FF 36/9.6) are compared to aplacebo and various different active compositions delivering a singleactive agent (one delivering only glycopyrrolate—GP 36, a seconddelivering only tiotropium bromide—Spiriva, and three delivering onlyformoterol fumarate—FF 7.2, FF 9.6, and Foradil).

FIG. 25 is a graph illustrating the FEV₁ AUC₀₋₁₂ on Day 7 for each ofthe active study compositions administered to patients as part of theclinical study described in Example 12. The improvement in FEV₁ AUC₀₋₁₂provided by each of the active study compositions relative to placebo isshown.

FIG. 26 is a graph illustrating the difference between the FEV₁ AUC₀₋₁₂achieved by the GP/FF 36/9.6 treatment on Day 7 relative to the GP 36,FF 9.6, Spiriva and Foradil active comparators. As can be easilyappreciated by reference to FIG. 26, the GP/FF 36/9.6 treatment providedsignificantly better improvements in FEV₁ AUC₀₋₁₂.

FIG. 27 is a graph showing the Peak FEV₁ on treatment day 1 (Day 1) andDay 7 achieved by various study compositions administered to patients aspart of the clinical study described in Example 12. The Peak FEV₁ shownrepresents the peak change in FEV₁ from baseline provided by each of theactive study composition relative to placebo on the study day indicated.

FIG. 28 is a graph illustrating the difference between the Peak FEV₁achieved by the GP/FF 36/9.6 treatment on Day 1 and Day 7 relative tothe Spiriva and Foradil active comparators. As can be easily appreciatedby reference to FIG. 28, the GP/FF 36/9.6 treatment providedsignificantly better improvements in Peak FEV₁ compared to the activecomparators.

FIG. 29 is a graph illustrating the improvements in Morning Trough FEV₁achieved by various study compositions administered to patients as partof the clinical study described in Example 12. The graph illustrates theimprovement in Morning Trough FEV₁ values provided by each of the activestudy compositions relative to placebo.

FIG. 30 is a graph showing the difference between the increase inpre-dose FEV₁ on Day 7 of the clinical study described in Example 12provided by two treatments using combination co-suspension compositionsas described herein (GP/FF 72/9.6 and GP/FF 36/9.6) relative to thedifferent single active agent comparators and to each other. As can beeasily appreciated by reference to FIG. 30, the GP/FF 72/9.6 and GP/FF36/9.6 treatments provided significantly better improvements in pre-doseFEV₁ compared to the single active agent comparators, but did not differsignificantly from each other.

FIG. 31 provides a graph illustrating the Day 1 and 7 peak, and Day 7pre-dose improvements in inspiratory capacity (IC) relative to placeboprovided by the two treatments using combination co-suspensioncompositions (GP/FF 72/9.6 and GP/FF 36/9.6) and the Spiriva activecomparator composition administered as part of the clinical trialdescribed in Example 12.

FIG. 32 provides a graph illustrating the consistent patient responseachieved in the clinical study described in Example 12 regardless of theseverity of the chronic obstructive pulmonary disease suffered by thepatients.

DETAILED DESCRIPTION

The present disclosure provides compositions, methods, and systems forrespiratory delivery of two or more active agents. Specifically, incertain embodiments, the present disclosure includes pharmaceuticalcompositions, systems and methods for respiratory delivery of two ormore active agents via an MDI, and in particular embodiments at leastone of the active agents is selected from long-acting muscarinicantagonist (“LAMA”), long-acting β₂ adrenergic agonist (“LABA”), andcorticosteroid active agents. The compositions described herein may beformulated for pulmonary or nasal delivery via an MDI. The methodsdescribed herein include methods of stabilizing formulations includingtwo or more active agents for respiratory delivery, as well as methodsfor pulmonary delivery of two or more active agents for treating apulmonary disease or disorder via an MDI. Also described herein are MDIsystems for delivery of two or more active agents, as well as methodsfor preparing such systems.

Formulating pharmaceutical compositions incorporating two or more activeagents is often challenging due to unpredictable or unexpectedinteractions between the active agents or changes to the formulationsresulting from the incorporation of multiple active agents. Suchinteractions are generally known as a “combination effect,” and in thecontext of suspension formulations delivered from an MDI, a combinationeffect may be manifest by, for example, a deviation from similaritybetween a formulation including a single active agent and a formulationincluding a combination of two or more active agents in one or more ofthe following areas: the aerosol and particle size distributioncharacteristics provided by the formulation; delivered dose uniformityfor one or more of the active agents; deliverability or absorption ofone or more of the active agents; or the dose proportionality observedfor one or more of the active agents.

In specific embodiments, the co-suspension compositions described hereinavoid combination effects associated with combination formulations. Forpurposes of the present description, a composition avoids combinationaffects where, for a selected active agent, the aerosol properties,particle size distribution characteristics, and delivered doseuniformity achieved by a combination formulation do not deviate fromthose achieved by a comparable formulation wherein the only active agentis the selected active agent. In some embodiments, the lack of acombination effect is evidenced for a selected active agent where theplasma concentration over time for a targeted dose of the selectedactive agent delivered from a combination formulation does not deviatefrom the plasma concentration over time achieved when the selectedactive agent is delivered at the same dose from a comparable formulationwherein the only active agent is the selected active agent.

As used herein, the phrases “do not deviate” or “does not deviate”signify that, for a given parameter, the performance achieved by acombination formulation is ±20% of that achieved by a comparableformulation including only one of the active agents included in thecombination formulation. In certain embodiments, the performanceachieved by a combination formulation does not vary from that achievedby a comparable formulation including only one of the active agentsincluded in the combination. For example, a co-suspension as describedherein, including two or more active agents, is considered to exhibit nocombination effect when, with respect to each such active agent at agiven dose, one or more of the aerosol properties, the particle sizedistribution characteristics, the delivered dose uniformity, and theplasma concentration over time achieved by the combination co-suspensionare within ±20% of those achieved by a comparable formulation includingonly a single active agent. In some embodiments, for each active agentat a give dose, one or more of the aerosol properties, the particle sizedistribution characteristics, the delivered dose uniformity, and theplasma concentration over time achieved by the combination co-suspensioncompositions described herein are within ±15% of those achieved by acomparable formulation including only a single active agent. In yetother embodiments, for each active agent at a give dose, one or more ofthe aerosol properties, the particle size distribution characteristics,the delivered dose uniformity, and the plasma concentration over timeachieved by the combination co-suspension compositions described hereinare within ±10% of those achieved by a comparable formulation includingonly a single active agent. In certain embodiments, with respect to eachactive agent at a given dose, the combination co-suspension compositionsas described herein exhibit no difference to comparable formulationsincluding only one of the active agents included in the combination inone or more of the following areas: aerosol properties for theformulation; the particle size distribution characteristics; delivereddose uniformity for; and the plasma concentration over time.

The combination of two or more active agents included in thecompositions provided herein may, in some embodiments, provideadvantages over pharmaceutical formulations including only a singleactive agent. For instance, when a combination of two or more activeagents is delivered simultaneously, the therapeutically effective doseof both active agents may be relatively less than when any of thecombined active agents is delivered alone, thereby avoiding or reducingpossible side effects. Moreover, combinations of two or more activeagents may achieve a more rapid onset or longer duration of therapeuticbenefit than can be achieved by delivering one of the combined activeagents alone.

In specific embodiments, the methods described herein include methodsfor treating a pulmonary disease or disorder amenable to treatment byrespiratory delivery of a co-suspension composition as described herein.For example, the compositions, methods and systems described herein canbe used to treat inflammatory or obstructive pulmonary diseases orconditions. In certain embodiments, the compositions, methods andsystems described herein can be used to treat patients suffering from adisease or disorder selected from asthma, chronic obstructive pulmonarydisease (COPD), exacerbation of airways hyper reactivity consequent toother drug therapy, allergic rhinitis, sinusitis, pulmonaryvasoconstriction, inflammation, allergies, impeded respiration,respiratory distress syndrome, pulmonary hypertension, pulmonaryvasoconstriction, and any other respiratory disease, condition, trait,genotype or phenotype that can respond to the administration of, forexample, a LAMA, LABA, corticosteroid, or other active agent asdescribed herein, whether alone or in combination with other therapies.In certain embodiments, the compositions, systems and methods describedherein can be used to treat pulmonary inflammation and obstructionassociated with cystic fibrosis. As used herein, the terms “COPD” and“chronic obstructive pulmonary disease” encompass chronic obstructivelung disease (COLD), chronic obstructive airway disease (COAD), chronicairflow limitation (CAL) and chronic obstructive respiratory disease(CORD) and include chronic bronchitis, bronchiectasis, and emphysema. Asused herein, the term “asthma” refers to asthma of whatever type orgenesis, including intrinsic (non-allergic) asthma and extrinsic(allergic) asthma, mild asthma, moderate asthma, severe asthma,bronchitic asthma, exercise-induced asthma, occupational asthma andasthma induced following bacterial infection. Asthma is also to beunderstood as embracing wheezy-infant syndrome.

When administered to patients suffering from pulmonary disease,embodiments of the co-suspension compositions described herein provide asignificant increase in one or more measures of lung function orcapacity when compared to compositions delivering only a single activeagent. In certain such embodiments, the delivery of a co-suspensioncomposition as described herein including two or more active agentsresults in a significant increase in one or both of FEV₁ and inspiratorycapacity (IC) relative to composition containing only a single activeagent.

It will be readily understood that the embodiments, as generallydescribed herein, are exemplary. The following more detailed descriptionof various embodiments is not intended to limit the scope of the presentdisclosure, but is merely representative of various embodiments. Assuch, the specifics recited herein may include independently patentablesubject matter. Moreover, the order of the steps or actions of themethods described in connection with the embodiments disclosed hereinmay be changed by those skilled in the art without departing from thescope of the present disclosure. In other words, unless a specific orderof steps or actions is required for proper operation of the embodiment,the order or use of specific steps or actions may be modified.

I. Definitions

Unless specifically defined otherwise, the technical terms, as usedherein, have their normal meaning as understood in the art. Thefollowing terms are specifically defined for the sake of clarity.

The term “active agent” is used herein to include any agent, drug,compound, composition or other substance that may be used on, oradministered to a human or animal for any purpose, includingtherapeutic, pharmaceutical, pharmacological, diagnostic, cosmetic andprophylactic agents and immunomodulators. The term “active agent” may beused interchangeably with the terms, “drug,” “pharmaceutical,”“medicament,” “drug substance,” or “therapeutic.” As used herein the“active agent” may also encompass natural or homeopathic products thatare not generally considered therapeutic.

The terms “associate,” “associate with” or “association” refers to aninteraction or relationship between a chemical entity, composition, orstructure in a condition of proximity to a surface, such as the surfaceof another chemical entity, composition, or structure. The associationincludes, for example, adsorption, adhesion, covalent bonding, hydrogenbonding, ionic bonding and electrostatic attraction, Lifshitz-van derWaals interactions and polar interactions. The term “adhere” or“adhesion” is a form of association and is used as a generic term forall forces tending to cause a particle or mass to be attracted to asurface. “Adhere” also refers to bringing and keeping particles incontact with each other, such that there is substantially no visibleseparation between particles due to their different buoyancies in apropellant under normal conditions. In one embodiment, a particle thatattaches to or binds to a surface is encompassed by the term “adhere.”Normal conditions may include storage at room temperature or under anaccelerative force due to gravity. As described herein, active agentparticles may associate with suspending particles to form aco-suspension, where there is substantially no visible separationbetween the suspending particles and the active agent particles orflocculates thereof due to differences in buoyancy within a propellant.

“Suspending particles” refer to a material or combination of materialsthat is acceptable for respiratory delivery, and acts as a vehicle foractive agent particles. Suspending particles interact with the activeagent particles to facilitate repeatable dosing, delivery or transportof active agent to the target site of delivery, i.e., the respiratorytract. The suspending particles described herein are dispersed within asuspension medium including a propellant or propellant system, and canbe configured according to any shape, size or surface characteristicsuited to achieving a desired suspension stability or active agentdelivery performance. Exemplary suspending particles include particlesthat exhibit a particle size that facilitates respiratory delivery ofactive agent and have physical configurations suited to formulation anddelivery of the stabilized suspensions as described herein.

The term “co-suspension” refers to a suspension of two or more types ofparticles having different compositions within a suspension medium,wherein one type of particle associates at least partially with one ormore of the other particle types. The association leads to an observablechange in one or more characteristics of at least one of the individualparticle types suspended in the suspension medium. Characteristicsmodified by the association may include, for example, one or more of therate of aggregation or flocculation, the rate and nature of separation,i.e. sedimentation or creaming, density of a cream or sediment layer,adhesion to container walls, adhesion to valve components, and rate andthe level of dispersion upon agitation.

Exemplary methods for assessing whether a co-suspension is present caninclude the following: If one particle type has a pycnometric densitygreater than the propellant and another particle type has a pycnometricdensity lower than the propellant, a visual observation of the creamingor sedimentation behavior can be employed to determine the presence of aco-suspension. The term “pycnometric density” refers to the density of amaterial that makes up a particle, excluding voids within the particle.In one embodiment, the materials can be formulated or transferred into atransparent vial, typically a glass vial, for visual observation. Afterinitial agitation the vial is left undisturbed for a sufficient time forformation of a sediment or cream layer, typically 24 hours. If thesediment or cream layer is observed to be completely or mostly a uniformsingle layer, a co-suspension is present. The term “co-suspension”includes partial co-suspensions, where a majority of the at least twoparticle types associate with each other, however, some separation(i.e., less than a majority) of the at least two particle types may beobserved.

The exemplary co-suspension test may be performed at differentpropellant temperatures to accentuate the sedimentation or creamingbehavior of particle types with a density close to the propellantdensity at room temperature. If the different particle types have thesame nature of separation, i.e. all sediment or all cream, the presenceof a co-suspension can be determined by measuring other characteristicsof the suspension, such as rate of aggregation or flocculation, rate ofseparation, density of cream or sediment layer, adhesion to containerwalls, adhesion to valve components, and rate and level of dispersionupon agitation, and comparing them to the respective characteristics ofthe similarly suspended individual particle types. Various analyticalmethods generally known to those skilled in the art can be employed tomeasure these characteristics.

In the context of a composition containing or providing respirableaggregates, particles, drops, etc., such as compositions describedherein, the term “fine particle dose” or “FPD” refers to the dose,either in total mass or fraction of the nominal dose or metered dose,that is within a respirable range. The dose that is within therespirable range is measured in vitro to be the dose that depositsbeyond the throat stage of a cascade impactor, i.e., the sum of dosedelivered at stages 3 through filter in a Next Generation Impactoroperated at a flow rate of 30 l/min.

In the context of a composition containing or providing respirableaggregates, particles, drops, etc., such as compositions describedherein, the term “fine particle fraction” or “FPF” refers to theproportion of the delivered material relative to the delivered dose(i.e., the amount that exits the actuator of a delivery device, such asan MDI) that is within a respirable range. The amount of deliveredmaterial within the respirable range is measured in vitro as the amountof material that deposits beyond the throat stage of a cascade impactor,e.g., the sum of the material delivered at stages 3 through filter in aNext Generation Impactor operated at a flow rate of 30 l/min.

As used herein, the term “inhibit” refers to a measurable lessening ofthe tendency of a phenomenon, symptom or condition to occur or thedegree to which that phenomenon, symptom or condition occurs. The term“inhibit” or any form thereof, is used in its broadest sense andincludes minimize, prevent, reduce, repress, suppress, curb, constrain,restrict, slow progress of and the like.

“Mass median aerodynamic diameter” or “MMAD” as used herein refers tothe aerodynamic diameter of an aerosol below which 50% of the mass ofthe aerosol consists of particles with an aerodynamic diameter smallerthan the MMAD, with the MMAD being calculated according to monograph 601of the United States Pharmacopeia (“USP”).

When referred to herein, the term “optical diameter” indicates the sizeof a particle as measured by the Fraunhofer diffraction mode using alaser diffraction particle size analyzer equipped with a dry powderdispenser (e.g., Sympatec GmbH, Clausthal-Zellerfeld, Germany).

The term solution mediated transformation refers to the phenomenon inwhich a more soluble form of a solid material (i.e. particles with smallradius of curvature (a driving force for Ostwald ripening), or amorphousmaterial) dissolves and recrystallizes into the more stable crystal formthat can coexist in equilibrium with its saturated propellant solution.

A “patient” refers to an animal in which a combination of active agentsas described herein will have a therapeutic effect. In one embodiment,the patient is a human being.

“Perforated microstructures” refer to suspending particles that includea structural matrix that exhibits, defines or comprises voids, pores,defects, hollows, spaces, interstitial spaces, apertures, perforationsor holes that allow the surrounding suspension medium to permeate, fillor pervade the microstructure, such as those materials and preparationsdescribed in U.S. Pat. No. 6,309,623 to Weers, et al. The primary formof the perforated microstructure is, generally, not essential, and anyoverall configuration that provides the desired formulationcharacteristics is contemplated herein. Accordingly, in one embodiment,the perforated microstructures may comprise approximately sphericalshapes, such as hollow, suspending, spray-dried microspheres. However,collapsed, corrugated, deformed or fractured particulates of any primaryform or aspect ratio may also be compatible.

As is true of suspending particles described herein, perforatedmicrostructures may be formed of any biocompatible material that doesnot substantially degrade or dissolve in the selected suspension medium.While a wide variety of materials may be used to form the particles, insome embodiments, the structural matrix is associated with, or includes,a surfactant such as, a phospholipid or fluorinated surfactant. Althoughnot required, the incorporation of a compatible surfactant in theperforated microstructure or, more generally, the suspending particles,can improve the stability of the respiratory dispersions, increasepulmonary deposition and facilitate the preparation of the suspension.

The term “suspension medium” as used herein refers to a substanceproviding a continuous phase within which active agent particles andsuspending particles can be dispersed to provide a co-suspensionformulation. The suspension medium used in co-suspension formulationsdescribed herein includes propellant. As used herein, the term“propellant” refers to one or more pharmacologically inert substanceswhich exert a sufficiently high vapor pressure at normal roomtemperature to propel a medicament from the canister of an MDI to apatient on actuation of the MDI's metering valve. Therefore, the term“propellant” refers to both a single propellant and to a combination oftwo or more different propellants forming a “propellant system.”

The term “respirable” generally refers to particles, aggregates, drops,etc. sized such that they can be inhaled and reach the airways of thelung.

When used to refer to co-suspension compositions described herein, theterms “physical stability” and “physically stable” refer to acomposition that is resistant to one or more of aggregation,flocculation, and particle size changes due to solution mediatedtransformations and is capable of substantially maintaining the MMAD ofsuspending particles and the fine particle dose. In one embodiment,physical stability may be evaluated through subjecting compositions toaccelerated degradation conditions, such as by temperature cycling asdescribed herein.

When referring to active agents, the term “potent” indicates activeagents that are therapeutically effective at or below doses ranging fromabout 0.01 mg/kg to about 1 mg/kg. Typical doses of potent active agentsgenerally range from about 100 μg to about 100 mg.

When referring to active agents, the term “highly potent” indicatesactive agents that are therapeutically effective at or below doses ofabout 10 μg/kg. Typical doses of highly potent active agents generallyrange up to about 100 μg.

The terms “suspension stability” and “stable suspension” refer tosuspension formulations capable of maintaining the properties of aco-suspension of active agent particles and suspending particles over aperiod of time. In one embodiment, suspension stability may be measuredthrough delivered dose uniformity achieved by co-suspension compositionsdescribed herein.

The term “substantially insoluble” means that a composition is eithertotally insoluble in a particular solvent or it is poorly soluble inthat particular solvent. The term “substantially insoluble” means that aparticular solute has a solubility of less than one part per 100 partssolvent. The term “substantially insoluble” includes the definitions of“slightly soluble” (from 100 to 1000 parts solvent per 1 part solute),“very slightly soluble” (from 1000 to 10,000 parts solvent per 1 partsolute) and “practically insoluble” (more than 10,000 parts solvent per1 part solute) as given in Table 16-1 of Remington: The Science andPractice of Pharmacy, 21st ed. Lippincott, Williams & Wilkins, 2006, p.212.

The term “surfactant,” as used herein, refers to any agent whichpreferentially adsorbs to an interface between two immiscible phases,such as the interface between water and an organic polymer solution, awater/air interface or organic solvent/air interface. Surfactantsgenerally possess a hydrophilic moiety and a lipophilic moiety, suchthat, upon adsorbing to microparticles, they tend to present moieties tothe continuous phase that do not attract similarly-coated particles,thus reducing particle agglomeration. In some embodiments, surfactantsmay also promote adsorption of a drug and increase bioavailability ofthe drug.

A “therapeutically effective amount” is the amount of compound whichachieves a therapeutic effect by inhibiting a disease or disorder in apatient or by prophylactically inhibiting or preventing the onset of adisease or disorder. A therapeutically effective amount may be an amountwhich relieves to some extent one or more symptoms of a disease ordisorder in a patient; returns to normal either partially or completelyone or more physiological or biochemical parameters associated with orcausative of the disease or disorder; and/or reduces the likelihood ofthe onset of the disease of disorder.

The terms “chemically stable” and “chemical stability” refer toco-suspension formulations wherein the individual degradation productsof active agent remain below the limits specified by regulatoryrequirements during the shelf life of the product for human use (e.g.,1% of total chromatographic peak area per ICH guidance Q3B(R2)) andthere is acceptable mass balance (e.g., as defined in ICH guidance Q1E)between active agent assay and total degradation products.

II. Compositions

The compositions described herein are co-suspensions that include two ormore active agents and include a suspension medium, one or more speciesof active agent particles, and one or more species of suspendingparticles. Of course, if desired, the compositions described herein mayinclude one or more additional constituents. Moreover, variations andcombinations of components of the compositions described herein may beused.

The co-suspension compositions according to the present description canbe embodied by various different formulations. In certain embodiments,the compositions described herein include a first active agent providedin active agent particles that are co-suspended with at least onespecies of suspending particles that incorporate a second active agent.In other embodiments, the compositions described herein include two ormore active agents provided in two or more different species of activeagent particles co-suspended with at least one species of suspendingparticles that incorporate an active agent different from that containedin any of the active agent particles. In yet further embodiments, thecompositions described herein include two or more active agents providedin two or more different species of active agent particles co-suspendedwith at least one species of suspending particles that incorporate anactive agent that may be the same as or different from that contained inany of the active agent particles. In still further embodiments, thecompositions described herein include two or more active agents providedin two or more different species of active agent particles co-suspendedwith one or more species of suspending particles that are free of activeagent. Where the compositions described herein include two or morespecies of active agent particles, such compositions may be referred toas “multi” co-suspensions. For example, a composition including twospecies of active agent particles co-suspended with one or more speciesof suspending particles may be referred to as a dual co-suspension, acomposition including three species of active agent particlesco-suspended with one or more species of suspending particles may bereferred to as a triple co-suspension, etc.

In compositions according to the present description, even when multipledifferent species of active agent particles are present in thecomposition, the active agent particles exhibit an association with thesuspending particles such that the active agent particles and suspendingparticles co-locate within the suspension medium. Generally, due todensity differences between distinct species of particles and the mediumwithin which they are suspended (e.g., a propellant or propellantsystem), buoyancy forces cause creaming of particles with lower densitythan the propellant and sedimentation of particles with higher densitythan the propellant. Therefore, in suspensions that consist of a mixtureof different types of particles with different density or differenttendencies to flocculate, sedimentation or creaming behavior is expectedto be specific to each of the different particle types and expected tolead to separation of the different particle types within the suspensionmedium.

However, the combinations of propellant, active agent particles, andsuspending particles described herein provide co-suspensions includingcombinations of two or more active agents wherein the active agentparticles and suspending particles co-locate within the propellant(i.e., the active agent particles associate with the suspendingparticles such that suspending particles and active agent particles donot exhibit substantial separation relative to each other, such as bydifferential sedimentation or creaming, even after a time sufficient forthe formation of a cream or sediment layer). In particular embodiments,for example, the compositions described herein form co-suspensionswherein the suspending particles remain associated with active agentparticles when subjected to buoyancy forces amplified by temperaturefluctuations and/or centrifugation at accelerations up to and over, forexample, 1 g, 10 g, 35 g, 50 g, and 100 g. However, the co-suspensionsdescribed herein need not be defined by a specific threshold force ofassociation. For example, a co-suspension as contemplated herein may besuccessfully achieved where the active agent particles associate withthe suspending particles such that there is no substantial separation ofactive agent particles and suspending particles within the continuousphase formed by the suspension medium under typical patient useconditions.

Co-suspensions of active agent particles and suspending particlesaccording to the present description provide desirable chemicalstability, suspension stability and active agent deliverycharacteristics. For example, in certain embodiments, when presentwithin an MDI canister, co-suspensions as described herein can inhibitone or more of the following: flocculation of active agent material;differential sedimentation or creaming of active agent particles andsuspending particles; solution mediated transformation of active agentmaterial; chemical degradation of a component of the formulation,including of active agent material or a surfactant; and loss of activeagent to the surfaces of the container closure system, in particular themetering valve components. Such qualities work to achieve and preserveaerosol performance as the co-suspension formulation is delivered froman MDI such that desirable fine particle fraction, fine particle doseand delivered dose uniformity characteristics are achieved andsubstantially maintained throughout emptying of an MDI canister withinwhich the co-suspension formulation is contained. Additionally,co-suspensions according to the present description can provide aphysically and chemically stable formulation that provides consistentdosing characteristics for two or more active agents, even where suchactive agents are delivered at significantly different doses, whileutilizing a relatively simple HFA suspension medium that does notrequire modification by the addition of, for example, cosolvents,antisolvents, solubilizing agents or adjuvants. Even further,compositions prepared as described herein, when delivered from an MDI,eliminate or substantially avoid the pharmaceutical effects oftenexperienced with formulations including multiple active agents. Forexample, as exemplified by specific embodiments detailed herein, thecombination formulations described herein provide deliverycharacteristics for each of the active agents contained thereincomparable to delivery characteristics of the same active agents whenformulated and delivered separately.

Providing a co-suspension according to the present description may alsosimplify formulation, delivery and dosing of the desired active agents.Without being bound by a particular theory, it is thought that byachieving a co-suspension of active agent particles and suspendingparticles, the delivery, physical stability, and dosing of an activeagent contained within such a dispersion may be substantially controlledthrough control of the size, composition, morphology and relative amountof the suspending particles, and is less dependent upon the size andmorphology of the particles of active agent. Moreover, in specificembodiments, the pharmaceutical compositions described herein can beformulated with a non-CFC propellant or propellant system substantiallyfree of antisolvents, solubilizing agents, cosolvents, or adjuvants.

Co-suspension compositions formulated according to the present teachingscan inhibit physical and chemical degradation of the active agentsincluded therein. For example, in specific embodiments, the compositionsdescribed herein may inhibit one or more of chemical degradation,flocculation, aggregation and solution mediated transformation of theactive agents included in the compositions. The chemical and suspensionstability provided by the co-suspension compositions described hereinallows the compositions to be dispensed in a manner that achievesdesirable delivered dose uniformity throughout emptying of an MDIcanister (“DDU”) for multiple active agents, even where at least one ofthe active agents to be delivered may be highly potent and the delivereddoses of each of the active agents vary considerably.

Co-suspension compositions as described herein, which include two ormore active agents, can achieve a DDU of ±30%, or better for each of theactive agents included therein. In one such embodiment, compositionsdescribed herein achieve a DDU of ±25%, or better, for each of theactive agents included therein. In another such embodiment, compositionsdescribed herein achieve a DDU of ±20%, or better, for each of theactive agents included therein. Moreover, co-suspension compositionsaccording to the present description serve to substantially preserve FPFand FPD performance throughout emptying of an MDI canister, even afterbeing subjected to accelerated degradation conditions. For instance,compositions according to the present description maintain as much as80%, 90%, 95%, or more, of the original FPF or FPD performance, evenafter being subjected to accelerated degradation conditions.

Co-suspension compositions described herein provide the added benefit ofachieving such performance while being formulated using non-CFCpropellants. In specific embodiments, the compositions described hereinachieve one or more of a targeted DDU, FPF or FPD, while beingformulated with suspension medium including only one or more non-CFCpropellants and without the need to modify the characteristics of thenon-CFC propellant, such as by the addition of, for example, one or morecosolvent, antisolvent, solubilizing agent, adjuvant or other propellantmodifying material.

(i) Suspension Medium

The suspension medium included in a composition described hereinincludes one or more propellants. In general, suitable propellants foruse as suspension mediums are those propellant gases that can beliquefied under pressure at room temperature, and upon inhalation ortopical use, are safe and toxicologically innocuous. Additionally, it isdesirable that the selected propellant be relatively non-reactive withthe suspending particles and active agent particles. Exemplarycompatible propellants include hydrofluoroalkanes (HFAs), perfluorinatedcompounds (PFCs), and chlorofluorocarbons (CFCs).

Specific examples of propellants that may be used to form the suspensionmedium of the co-suspensions disclosed herein include1,1,1,2-tetrafluoroethane (CF₃CH₂F) (HFA-134a),1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃CHFCF₃) (HFA-227),perfluoroethane, monochloro-fluoromethane, 1,1 difluoroethane, andcombinations thereof. Even further, suitable propellants include, forexample: short chain hydrocarbons; C₁₋₄ hydrogen-containingchlorofluorocarbons such as CH₂ClF, CCl₂FCHClF, CF₃CHClF, CHF₂CClF₂,CHClFCHF₂, CF₃CH₂Cl, and CClF₂CH₃; C₁₋₄ hydrogen-containingfluorocarbons (e.g., HFAs) such as CHF₂CHF₂, CF₃CH₂F, CHF₂CH₃, andCF₃CHFCF₃; and perfluorocarbons such as CF₃CF₃ and CF₃CF₂CF₃.

Specific fluorocarbons, or classes of fluorinated compounds, that may beused as suspension media include, but are not limited to, fluoroheptane,fluorocycloheptane, fluoromethylcycloheptane, fluorohexane,fluorocyclohexane, fluoropentane, fluorocyclopentane,fluoromethylcyclopentane, fluorodimethyl-cyclopentanes,fluoromethylcyclobutane, fluorodimethylcyclobutane,fluorotrimethyl-cyclobutane, fluorobutane, fluorocyclobutane,fluoropropane, fluoroethers, fluoropolyethers and fluorotriethylamines.These compounds may be used alone or in combination with more volatilepropellants.

In addition to the aforementioned fluorocarbons and hydrofluoroalkanes,various exemplary chlorofluorocarbons and substituted fluorinatedcompounds may also be used as suspension media. In this respect, FC-11(CCl₃F), FC-11B1 (CBrCl₂F), FC-11B2 (CBr₂ClF), FC12B2 (CF₂Br₂), FC21(CHCl₂F), FC21B1 (CHBrClF), FC-21B2 (CHBr₂F), FC-31B1 (CH₂BrF), FC113A(CCl₃CF₃), FC-122 (CClF₂CHCl₂), FC-123 (CF₃CHCl₂), FC-132 (CHClFCHClF),FC-133 (CHClFCHF₂), FC-141 (CH₂ClCHClF), FC-141B (CCl₂FCH₃), FC-142(CHF₂CH₂Cl), FC-151 (CH₂FCH₂Cl), FC-152 (CH₂FCH₂F), FC-1112 (CClF═CClF),FC-1121 (CHCl═CFCl) and FC-1131 (CHCl═CHF) may also be used, whilerecognizing the possible attendant environmental concerns. As such, eachof these compounds may be used, alone or in combination with othercompounds (i.e., less volatile fluorocarbons) to form the stabilizedsuspensions disclosed herein.

In some embodiments, the suspension medium may be formed of a singlepropellant. In other embodiments, a combination of propellants may beused to form the suspension medium. In some embodiments, relativelyvolatile compounds may be mixed with lower vapor pressure components toprovide suspension media having specified physical characteristicsselected to improve stability or enhance the bioavailability of thedispersed active agents. In some embodiments, the lower vapor pressurecompounds will comprise fluorinated compounds (e.g. fluorocarbons)having a boiling point greater than about 25° C. In some embodiments,lower vapor pressure fluorinated compounds for use in the suspensionmedium may include perfluorooctylbromide C₈F₁₇Br (PFOB or perflubron),dichlorofluorooctane C₈F₁₆Cl₂, perfluorooctylethane C₈F₁₇C₂H₅ (PFOE),perfluorodecylbromide C₁₀F₂₁Br (PFDB) or perfluorobutylethane C₄F₉C₂H₅.In certain embodiments, these lower vapor pressure compounds are presentin a relatively low level. Such compounds may be added directly to thesuspension medium or may be associated with the suspending particles.

The suspension medium included in compositions as described herein maybe formed of a propellant or propellant system that is substantiallyfree of additional materials, including, for example, antisolvents,solubilizing agents, cosolvents or adjuvants. For example, in someembodiments, the suspension medium may be formed of a non-CFC propellantor propellant system, such as an HFA propellant or propellant system,that is substantially free of additional materials. Such embodimentssimplify the formulation and manufacture of pharmaceutical compositionssuited for respiratory delivery of the active agents included in theco-suspension compositions.

However, in other embodiments, depending on the selection of propellant,the properties of the suspending particles, or the nature of the activeagents to be delivered, the suspension medium utilized may includematerials in addition to the propellant or propellant system. Suchadditional materials may include, for example, one or more of anappropriate antisolvent, solubilizing agent, cosolvent or adjuvant toadjust, for example, the vapor pressure of the formulation or thestability, or solubility of suspended particles. For example, propane,ethanol, isopropyl alcohol, butane, isobutane, pentane, isopentane or adialkyl ether, such as dimethyl ether, may be incorporated with thepropellant in the suspension medium. Similarly, the suspension mediummay contain a volatile fluorocarbon. In other embodiments, one or bothof polyvinylpyrrolidone (“PVP”) or polyethylene glycol (“PEG”) may beadded to the suspension medium. Adding PVP or PEG to the suspensionmedium may achieve one or more desired functional characteristics, andin one example, PVP or PEG may be added to the suspension medium as acrystal growth inhibitor. In general, where a volatile cosolvent oradjuvant is used, such an adjuvant or cosolvent may be selected fromknown hydrocarbon or fluorocarbon materials and may account for up toabout 1% w/w of the suspension medium. For example, where a cosolvent oradjuvant is incorporated in the suspension medium, the cosolvent oradjuvant may comprise less than about 0.01%, 0.1%, or 0.5% w/w of thesuspension medium. Where PVP or PEG are included in the suspensionmedium, such constituents may be included at up to about 1% w/w, or theymay comprise less than about 0.01%, 0.1%, or 0.5% w/w of the suspensionmedium.

(ii) Active Agent Particles

The active agent particles included in the co-suspensions describedherein are formed of a material capable of being dispersed and suspendedwithin the suspension medium and are sized to facilitate delivery ofrespirable particles from the co-suspension. In one embodiment,therefore, the active agent particles are provided as a micronizedmaterial wherein at least 90% of the active agent particles by volumeexhibit an optical diameter of about 7 μm or less. In other embodiments,the active agent particles are provided as a micronized material whereinat least 90% of the active agent particles by volume exhibit an opticaldiameter selected from a range of about 7 μm to about 1 μm, about 5 μmto about 2 μm, and about 3 μm to about 2 μm. In other embodiments, theactive agent particles are provided as a micronized material wherein atleast 90% of the active agent particles by volume exhibit an opticaldiameter selected from 6 μm or less, 5 μm or less, 4 μm or less, or 3 μmor less. In another embodiment, the active agent particles are providedas a micronized material wherein at least 50% of the active agentparticle material by volume exhibits an optical diameter of about 4 μmor less. In further embodiments, the active agent particles are providedas a micronized material wherein at least 50% of the active agentparticle material by volume exhibits an optical diameter selected fromabout 3 μm or less, about 2 μm or less, about 1.5 μm or less, and about1 μm or less. In still further embodiments, the active agent particlesare provided as a micronized material wherein at least 50% of the activeagent particles by volume exhibit an optical diameter selected from arange of about 4 μm to about 1 μm, about 3 μm to about 1 μm, about 2 μmto about 1 μm, about 1.3 μm, and about 1.9 μm.

The active agent particles may be formed entirely of active agent orthey may be formulated to include one or more active agents incombination with one or more excipients or adjuvants. In specificembodiments, an active agent present in the active agent particles maybe entirely or substantially crystalline, i.e., a majority of the activeagent molecules are arranged in a regularly repeating pattern, over along range of external face planes. In another embodiment, the activeagent particles may include an active agent present in both crystal andamorphous states. In yet another embodiment, the active agent particlesmay include an active agent present in substantially an amorphous state,i.e., the active agent molecules are overall noncrystalline in natureand do not have a regularly repeating arrangement maintained over a longrange. In yet a further embodiment, where two or more active agents arepresent as active agent particles, all such active agents may be presentin crystalline or substantially crystalline form. In alternativeembodiments with two or more active agents present, at least one suchactive agent may be present in crystalline or substantially crystallineform and at least another active agent may be present in an amorphousstate.

Where the active agent particles described herein include two or moreactive agents in combination with one or more excipients or adjuvants,the excipients and adjuvants can be selected based on the chemical andphysical properties of the active agents used. Moreover, suitableexcipients for the formulation of active agent particles include thosedescribed herein in association with the suspending particles. Inspecific embodiments, for example, active agent particles may beformulated with one or more of the lipid, phospholipid, carbohydrate,amino acid, organic salt, peptide, protein, alditols, synthetic ornatural polymer, or surfactant materials as described, for example, inassociation with the suspending particles.

In other embodiments, for example, an active agent may be added to asolution of one or more of the lipid, phospholipid, carbohydrate, aminoacid, metal salt, organic salt, peptide, protein, alditols, synthetic ornatural polymer, or surfactant materials and spray-dried into asuspending particle that contains the active agent within the materialforming the suspending particle.

Any suitable process may be employed to achieve micronized active agentmaterial for use as or inclusion in active agent particles or suspendingparticles as described herein. Such processes include, but are notlimited to, micronization by milling or grinding processes,crystallization or recrystallization processes, and processes usingprecipitation from supercritical or near-supercritical solvents, spraydrying, spray freeze-drying, or lyophilization. Patent referencesteaching suitable methods for obtaining micronized active agentparticles are described, for example, in U.S. Pat. Nos. 6,063,138,5,858,410, 5,851,453, 5,833,891, 5,707,634, and International PatentPublication No. WO 2007/009164. Where the active agent particles includeactive agent material formulated with one or more excipient or adjuvant,micronized active agent particles can be formed using one or more of thepreceding processes and such processes can be utilized to achieve activeagent particles having a desired size distribution and particleconfiguration.

The active agent particles may be provided in any suitable concentrationwithin the suspension medium. For example, in some embodiments, theactive agent particles may be present in concentrations between about0.01 mg/ml and about 20 mg/ml. In certain such embodiments, the activeagent particles may be present in a concentration selected from about0.05 mg/ml to about 20 mg/ml, about 0.05 mg/ml to about 10 mg/ml, andfrom about 0.05 mg/ml to about 5 mg/ml.

A variety of therapeutic or prophylactic agents can be utilized asactive in the co-suspension compositions disclosed herein. Exemplaryactive agents include those that may be administered in the form ofaerosolized medicaments, and active agents suitable for use in thecompositions described herein include those that may be presented in aform or formulated in a manner which is dispersible within the selectedsuspension medium (e.g., is substantially insoluble or exhibits asolubility in the suspension medium that substantially maintains aco-suspension formulation), is capable of forming a co-suspension withthe suspending particles, and is subject to respirable uptake inphysiologically effective amounts. The active agents that may beutilized in forming the active agent particles described herein can havea variety of biological activities.

Examples of specific active agents that may be included in a compositionaccording to the present description may for example, short-acting betaagonists, e.g., bitolterol, carbuterol, fenoterol, hexoprenaline,isoprenaline (isoproterenol), levosalbutamol, orciprenaline(metaproterenol), pirbuterol, procaterol, rimiterol, salbutamol(albuterol), terbutaline, tulobuterol, reproterol, ipratropium andepinephrine; long-acting β₂ adrenergic receptor agonist (“LABA”), e.g.,bambuterol, clenbuterol, formoterol, salmeterol; ultra long-acting β₂adrenergic receptor agonists, e.g., carmoterol, milveterol, indacaterol,and saligenin- or indole-containing and adamantyl-derived β₂ agonists;corticosteroids, e.g., beclomethasone, budesonide, ciclesonide,flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisoneand trimacinolone; anti-inflammatories, e.g. fluticasone propionate,beclomethasone dipropionate, flunisolide, budesonide, tripedane,cortisone, prednisone, prednisilone, dexamethasone, betamethasone, ortriamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators,e.g., ephedrine, adrenaline, fenoterol, formoterol, isoprenaline,metaproterenol, salbutamol, albuterol, salmeterol, terbutaline; andmuscarinic antagonists, including long-acting muscarinic antagonists(“LAMA”), e.g., glycopyrrolate, dexipirronium, scopolamine, tropicamide,pirenzepine, dimenhydrinate, tiotropium, darotropium, aclidinium,trospium, ipatropium, atropine, benzatropin, or oxitropium.

Where appropriate, the active agents provided in the composition,including but not limited to those specifically described herein, may beused in the form of salts (e.g., alkali metal or amine salts or as acidaddition salts) or as esters, solvates (hydrates), derivatives, or afree base. Additionally, the active agents may be in any crystallineform or isomeric form or mixture of isomeric forms, for example, as pureenantiomers, a mixture of enantiomers, as racemates or as mixturesthereof. In this regard, the form of the active agents may be selectedto optimize the activity and/or stability of the active agent and/or tominimize the solubility of the active agent in the suspension medium.

Because the compositions disclosed provide reproducible delivery of verylow doses of active agents, in certain embodiments, the active agentsincluded in the compositions described herein may be selected from oneor more potent or highly potent active agents. For example, in certainembodiments, the compositions described herein may include one or morepotent active agents that are to be delivered at a dose selected frombetween about 100 μg and about 100 mg per dose, about 100 μg and about10 mg per dose, and about 100 μg and 1 mg per dose. In otherembodiments, the compositions described herein may include a combinationof two or more potent or highly potent active agents that are to bedelivered at a dose selected from up to about 80 μg per dose, up toabout 40 μg per dose, up to about 20 μg per dose, up to about 10 μg perdose or between about 10 μg and about 100 μg per dose. Additionally, incertain embodiments, the compositions described herein may include acombination of two or more highly potent active agents that are to bedelivered at a dose selected from between about 0.1 and about 2 μg perdose, about 0.1 and about 1 μg per dose, and about 0.1 and about 0.5 μgper dose.

In certain embodiments, the compositions described herein include a LABAactive agent. In one such embodiment, the composition includes a LABAactive agent in combination with a LAMA active agent or a corticosteroidactive agent. In another such embodiment, the composition includes aLAMA active agent in combination with a LABA active agent and acorticosteroid. In such embodiments, a LABA active agent can be selectedfrom, for example, bambuterol, clenbuterol, formoterol, salmeterol,carmoterol, milveterol, indacaterol, and saligenin- or indole-containingand adamantyl-derived β₂ agonists, and any pharmaceutically acceptablesalts, esters, isomers or solvates thereof. In certain such embodiments,the active agent is selected from formoterol and its pharmaceuticallyacceptable salts, esters, isomers or solvates thereof.

Formoterol can be used to treat inflammatory or obstructive pulmonarydiseases and disorders such as, for example, those described herein.Formoterol has the chemical name(±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide, and is commonly used in pharmaceutical compositions as theracemic fumarate dihydrate salt. Where appropriate, formoterol may beused in the form of salts (e.g. alkali metal or amine salts or as acidaddition salts) or as esters or as solvates (hydrates). Additionally,the formoterol may be in any crystalline form or isomeric form ormixture of isomeric forms, for example a pure enantiomer, a mixture ofenantiomers, a racemate or a mixture thereof. In this regard, the formof formoterol may be selected to optimize the activity and/or stabilityof formoterol and/or to minimize the solubility of formoterol in thesuspension medium. Pharmaceutically acceptable salts of formoterolinclude, for example, salts of inorganic acids such as hydrochloric,hydrobromic, sulfuric and phosphoric acids, and organic acids such asfumaric, maleic, acetic, lactic, citric, tartaric, ascorbic, succinic,glutaric, gluconic, tricarballylic, oleic, benzoic, p-methoxybenzoic,salicylic, o- and p-hydroxybenzoic, p-chlorobenzoic, methanesulfonic,p-toluenesulfonic and 3-hydroxy-2-naphthalene carboxylic acids. Hydratesof formoterol are described, for example, in U.S. Pat. Nos. 3,994,974and 5,684,199. Specific crystalline forms are described, for example, inWO95/05805, and specific isomers of formoterol are described in U.S.Pat. No. 6,040,344.

In specific embodiments, the formoterol material utilized to form theformoterol particles is formoterol fumarate, and in one such embodiment,the formoterol fumarate is present in the dihydrate form. Where thecompositions described herein include formoterol, in certainembodiments, the compositions described herein may include formoterol ata concentration that achieves a delivered dose selected from betweenabout 0.5 μg and about 30 μg, 0.5 μg and about 1 μg, about 1 μg andabout 10 μg, about 2 μg and 5 μg, about 2 μg and about 10 μg, about 5and about 10 μg, and 3 μg and about 30 μg per actuation of an MDI. Inother embodiments, the compositions described herein may includeformoterol in an amount sufficient to provide a delivered dose selectedfrom up to about 30 μg, up to about 10 μg, up to about 5 μg, up to about2.5 μg, up to about 2 μg, or up to about 1.5 μg per actuation of an MDI.In order to achieve delivered doses as described herein, wherecompositions described herein include formoterol as the active agent, inspecific embodiments, the amount of formoterol included in thecompositions may be selected from, for example, between about 0.01 mg/mland about 1 mg/ml, between about 0.01 mg/ml and about 0.5 mg/ml, andbetween about 0.03 mg/ml and about 0.4 mg/ml.

Where the pharmaceutical co-suspension compositions described hereininclude a LABA active agent, in certain embodiments, the active agent isselected from salmeterol, including any pharmaceutically acceptablesalts, esters, isomers or solvates thereof. Salmeterol can be used totreat inflammatory or obstructive pulmonary diseases and disorders suchas, for example, those described herein. Again, where salmerterol isincluded as the LABA active agent, in some such embodiments, thecompositions may also include a LAMA or corticosteroid active agent. Inother such embodiments, the compositions include salmeterol incombination with a LAMA active agent and a corticosteroid. Salmeterol,pharmaceutically acceptable salts of salmeterol, and methods forproducing the same are described, for example, in U.S. Pat. Nos.4,992,474, 5,126,375, and 5,225,445.

Where salmeterol is included as a LABA active agent, in certainembodiments, the compositions described herein may include salmeterol ata concentration that achieves a delivered dose selected from betweenabout 2 μg and about 120 μg, about 4 μg and about 40 μg, about 8 μg and20 μg, about 8 μg and about 40 μg, about 20 μg and about 40 μg, andabout 12 μg and about 120 μg per actuation of an MDI. In otherembodiments, the compositions described herein may include salmeterol inan amount sufficient to provide a delivered dose selected from up toabout 120 μg, up to about 40 μg, up to about 20 μg, up to about 10 μg,up to about 8 μg, or up to about 6 μg per actuation of an MDI. In orderto achieve targeted delivered doses as described herein, wherecompositions described herein include salmeterol as the active agent, inspecific embodiments, the amount of salmeterol included in thecompositions may be selected from, for example, between about 0.04 mg/mland about 4 mg/ml, between about 0.04 mg/ml and about 2.0 mg/ml, andbetween about 0.12 mg/ml and about 0.8 mg/ml. For example, thecompositions described herein may include sufficient salmeterol toprovide a target delivered dose selected from between about 4 μg andabout 120 μg, about 20 μg and about 100 μg, and between about 40 μg andabout 120 μg per actuation of an MDI. In still other embodiments, thecompositions described herein may include sufficient salmeterol toprovide a targeted delivered dose selected from up to about 100 μg, upto about 40 μg, or up to about 15 μg per actuation of an MDI.

In certain embodiments, the compositions described herein include along-acting muscarinic antagonist (LAMA) active agent. Examples of LAMAactive agents that may be used in the compositions described hereininclude, glycopyrrolate, dexipirronium, tiotropium, trospium, aclidiniumand darotropium, including any pharmaceutically acceptable salts,esters, isomers or solvates thereof. In some embodiments, thecompositions described herein include a LAMA active agent in combinationwith a LABA active agent or a corticosteroid. In other such embodiments,the compositions described herein include a LAMA active agent incombination with both LABA and corticosteroid active agents. Where thecompositions include a LAMA active agent, in particular embodiments,glycopyrrolate, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, may be selected.

Glycopyrrolate can be used to treat inflammatory or obstructivepulmonary diseases and disorders such as, for example, those describedherein. As an anticholinergic, glycopyrrolate provides an antisecretoryeffect, which is a benefit for use in the therapy of pulmonary diseasesand disorders characterized by increased mucus secretions.Glycopyrrolate is a quaternary ammonium salt. Where appropriate,glycopyrrolate may be used in the form of salts (e.g. alkali metal oramine salts, or as acid addition salts), esters, solvates (hydrates), orselected isomers. Additionally, the glycopyrrolate may be in anycrystalline form or isomeric form or mixture of isomeric forms, forexample a pure enantiomer, a mixture of enantiomers, a racemate or amixture thereof. In this regard, the form of glycopyrrolate may beselected to optimize the activity and/or stability of glycopyrrolateand/or to minimize the solubility of glycopyrrolate in the suspensionmedium. Suitable counter ions are pharmaceutically acceptable counterions including, for example, fluoride, chloride, bromide, iodide,nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate,propionate, butyrate, lactate, citrate, tartrate, malate, maleate,succinate, benzoate, p-chlorobenzoate, diphenyl-acetate ortriphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate,1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate,methanesulfonate and benzenesulfonate. In particular embodiments of thecompositions described herein, the bromide salt of glycopyrrolate,namely3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidiniumbromide, is used and can be prepared according to the procedures set outin U.S. Pat. No. 2,956,062.

Where the compositions described herein include glycopyrrolate, incertain embodiments, the compositions may include sufficientglycopyrrolate to provide a delivered dose selected from between about10 μg and about 100 μg, about 15 μg and about 100 μg, about 15 μg andabout 80 μg, and about 10 μg and about 80 μg per actuation of an MDI. Inother such embodiments, the formulations include sufficientglycopyrrolate to provide a delivered dose selected from up to about 100μg, up to about 80 μg, up to about 40 μg, up to about 20 μg, or up toabout 10 μg per actuation of an MDI. In yet further embodiments, theformulations include sufficient glycopyrrolate to provide a delivereddose selected from about 9 μg, 18 μg, 36 μg and 72 μg per actuation ofthe MDI. In order to achieve delivered doses as described herein, wherecompositions described herein include glycopyrrolate as the activeagent, in specific embodiments, the amount of glycopyrrolate included inthe compositions may be selected from, for example, between about 0.04mg/ml and about 2.25 mg/ml.

In other embodiments, tiotropium, including any pharmaceuticallyacceptable salts, esters, isomers or solvates thereof, may be selectedas a LAMA active agent for inclusion in a composition as describedherein. Tiotropium is a known, long-acting anticholinergic drug suitablefor use in treating diseases or disorders associated with pulmonaryinflammation or obstruction, such as those described herein. Tiotropium,including crystal and pharmaceutically acceptable salt forms oftiotropium, is described, for example, in U.S. Pat. Nos. 5,610,163,RE39820, 6,777,423, and 6,908,928. Where the compositions describedherein include tiotropium, in certain embodiments, the compositions mayinclude sufficient tiotropium to provide a delivered dose selected frombetween about 2.5 μg and about 25 μg, about 4 μg and about 25 μg, about2.5 μg and about 20 μg, and about 10 μg and about 20 μg per actuation ofan MDI. In other such embodiments, the formulations include sufficienttiotropium to provide a delivered dose selected from up to about 25 μg,up to about 20 μg, up to about 10 μg, up to about 5 μg, or up to about2.5 μg per actuation of an MDI. In yet further embodiments, theformulations include sufficient tiotropium to provide a delivered doseselected from about 3 μg, 6 μg, 9 μg, and 18 μg per actuation of theMDI. In order to achieve delivered doses as described herein, wherecompositions described herein include tiotropium as the active agent, inspecific embodiments, the amount of tiotropium included in thecompositions may be selected from, for example, between about 0.01 mg/mland about 0.5 mg/ml.

In still other embodiments, the compositions described herein include acorticosteroid. Such active agents may be selected from, for example,beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone,methyl-prednisolone, mometasone, prednisone and trimacinolone, includingany pharmaceutically acceptable salts, esters, isomers or solvatesthereof. In some embodiments, such compositions include a corticosteroidactive agent in combination with a LAMA or LABA active agent. In othersuch embodiments, the compositions include a corticosteroid active agentin combination with a LAMA and a LABA active agent. Where thecompositions include a corticosteroid active agent, in particularembodiments, mometasone may be selected

Mometasone, pharmaceutically acceptable salts of mometasone, such asmometasone furoate, and preparation of such materials are known, anddescribed, for example, in U.S. Pat. Nos. 4,472,393, 5,886,200, and6,177,560. Mometasone is suitable for use in treating diseases ordisorders associated with pulmonary inflammation or obstruction, such asthose described herein (see, e.g., U.S. Pat. Nos. 5,889,015, 6,057,307,6,057,581, 6,677,322, 6,677,323 and 6,365,581).

Where the compositions described herein include mometasone, inparticular embodiments, the compositions include mometasone, includingany pharmaceutically acceptable salts, esters, isomers or solvatesthereof, in an amount sufficient to provide a target delivered doseselected from between about 20 μg and about 400 μg, about 20 μg andabout 200 μg, about 50 μg and about 200 μg, about 100 μg and about 200μg, about 20 μg and about 100 μg, and about 50 μg and about 100 μg, peractuation of an MDI. In still other embodiments, the compositionsdescribed herein may include mometasone, including any pharmaceuticallyacceptable salts, esters, isomers or solvates thereof, in an amountsufficient to provide a targeted delivered dose selected from up toabout 400 μg, up to about 200 μg, or up to about 100 μg per actuation ofan MDI.

In other embodiments, the compositions described herein include acorticosteroid selected from fluticasone and budesonide. Bothfluticasone and budesonide are suitable for use in treatment ofconditions associated with pulmonary inflammation or obstruction, suchas those described herein. Fluticasone, pharmaceutically acceptablesalts of fluticasone, such as fluticasone propionate, and preparation ofsuch materials are known, and described, for example, in U.S. Pat. Nos.4,335,121, 4,187,301, and U.S. Pat. Pub. No. US2008125407. Budesonide isalso well known and described, for example, in U.S. Pat. No. 3,929,768.In certain embodiments, compositions described herein may includefluticasone, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, in an amount sufficient to provide a targetdelivered dose selected from between about 20 μg and about 200 μg, about50 μg and about 175 μg, and between about 80 μg and about 160 μg peractuation of an MDI. In other embodiments, the compositions describedherein may include fluticasone, including any pharmaceuticallyacceptable salts, esters, isomers or solvates thereof, in an amountsufficient to provide a targeted delivered dose selected from up toabout 175 μg, up to about 160 μg, up to about 100 μg, or up to about 80μg per actuation of an MDI. In particular embodiments, compositionsdescribed herein may include budesonide, including any pharmaceuticallyacceptable salts, esters, isomers or solvates thereof, in an amountsufficient to provide target delivered dose selected from between about30 μg and about 240 μg, about 30 μg and about 120 μg, and between about30 μg and about 50 μg per actuation of an MDI. In still otherembodiments, the compositions described herein may include budesonide,including any pharmaceutically acceptable salts, esters, isomers orsolvates thereof, in an amount sufficient to provide a targeteddelivered dose selected from up to about 240 μg, up to about 120 μg, orup to about 50 μg per actuation of an MDI.

In each embodiment, a composition as described herein includes two ormore active agents. In some embodiments, the compositions include acombination of two or more species of active agent particles which maybe co-suspended with a single species of suspending particles.Alternatively, a composition may include two or more species of activeagent particles co-suspended with two or more different species ofsuspending particles. As yet another alternative, compositions asdescribed herein may include a single species of active agent particlessuspended with a single species of suspending particles, wherein thesingle species of active agent particles incorporates one or more activeagents and the single species of suspending particles incorporates oneor more active agents. Even further, a composition as described hereinmay include two or more active agents combined within a single speciesof active agent particle. For example, where the active agent particlesare formulated using one or more excipients or adjuvants in addition tothe active agent material, such active agent particles may includeindividual particles that include two or more different active agents.

(iii) Suspending Particles

The suspending particles included in the co-suspension compositionsdescribed herein work to facilitate stabilization and delivery of theactive agent included in the compositions. Though various forms ofsuspending particles may be used, the suspending particles are typicallyformed from pharmacologically inert material that is acceptable forinhalation and is substantially insoluble in the propellant selected.Generally, the majority of suspending particles are sized within arespirable range. In particular embodiments, therefore, the MMAD of thesuspending particles will not exceed about 10 μm but is not lower thanabout 500 μm. In an alternative embodiment, the MMAD of the suspendingparticles is between about 5 μm and about 750 μm. In yet anotherembodiment, the MMAD of the suspending particles is between about 1 μmand about 3 μm. When used in an embodiment for nasal delivery from anMDI, the MMAD of the suspending particles is between 10 μm and 50 μm.

In order to achieve respirable suspending particles within the MMADranges described, the suspending particles will typically exhibit avolume median optical diameter between about 0.2 μm and about 50 μm. Inone embodiment, the suspending particles exhibit a volume median opticaldiameter that does not exceed about 25 μm. In another embodiment, thesuspending particles exhibit a volume median optical diameter selectedfrom between about 0.5 μm and about 15 μm, between about 1.5 μm andabout 10 μm, and between about 2 μm and about 5 μm.

The concentration of suspending particles included in a compositionaccording to the present description can be adjusted, depending on, forexample, the amount of active agent particles and suspension mediumused. In one embodiment, the suspending particles are included in thesuspension medium at a concentration selected from about 1 mg/ml toabout 15 mg/ml, about 3 mg/ml to about 10 mg/ml, 5 mg/ml to about 8mg/ml, and about 6 mg/ml. In another embodiment, the suspendingparticles are included in the suspension medium at a concentration of upto about 30 mg/ml. In yet another embodiment, the suspending particlesare included in the suspension medium at a concentration of up to about25 mg/ml.

The relative amount of suspending particles to active agent particles isselected to achieve a co-suspension as contemplated herein. Aco-suspension composition may be achieved where the amount of suspendingparticles, as measured by mass, exceeds that of the active agentparticles. For example, in specific embodiments, the ratio of the totalmass of the suspending particles to the total mass of active agentparticles may be between about 3:1 and about 15:1, or alternatively fromabout 2:1 and 8:1. Alternatively, the ratio of the total mass of thesuspending particles to the total mass of active agent particles may beabove about 1, such as up to about 1.5, up to about 5, up to about 10,up to about 15, up to about 17, up to about 20, up to about 30, up toabout 40, up to about 50, up to about 60, up to about 75, up to about100, up to about 150, and up to about 200, depending on the nature ofthe suspending particles and active agent particles used. In furtherembodiments, the ratio of the total mass of the suspending particles tothe total mass of the active agent particles may be selected frombetween about 10 and about 200, between about 60 and about 200, betweenabout 15 and about 60, between about 15 and about 170, between about 15and about 60, about 16, about 60, and about 170.

In other embodiments, the amount of suspending particles, as measured bymass, is less than that of the active agent particles. For example, inparticular embodiments, the mass of the suspending particles may be aslow as 20% of the total mass of the active agent particles. However, insome embodiments, the total mass of the suspending particles may alsoapproximate or equal the total mass of the active agent particles.

Suspending particles suitable for use in the compositions describedherein may be formed of one or more pharmaceutically acceptablematerials or excipients that are suitable for inhaled delivery and donot substantially degrade or dissolve in the suspension medium. In oneembodiment, perforated microstructures, as defined herein, may be usedas the suspending particles. Exemplary excipients that may be used inthe formulation of suspending particles described herein include but arenot limited to (a) carbohydrates, e.g., monosaccharides such asfructose, galactose, glucose, D-mannose, sorbose, and the like;disaccharides, such as sucrose, lactose, trehalose, cellobiose, and thelike; cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin; andpolysaccharides, such as raffinose, maltodextrins, dextrans, starches,chitin, chitosan, inulin, and the like; (b) amino acids, such asalanine, glycine, arginine, aspartic acid, glutamic acid, cysteine,lysine, leucine, isoleucine, valine, and the like; (c) metal and organicsalts prepared from organic acids and bases, such as sodium citrate,sodium ascorbate, magnesium gluconate, sodium gluconate, tromethaminhydrochloride, and the like; (d) peptides and proteins such asaspartame, trileucine, human serum albumin, collagen, gelatin, and thelike; (e) alditols, such as mannitol, xylitol, and the like; (f)synthetic or natural polymers or combinations thereof, such aspolylactides, polylactide-glycolides, cyclodextrins, polyacrylates,methylcellulose, carboxymethylcellulose, polyvinyl alcohols,polyanhydrides, polylactams, polyvinyl pyrrolidones, hyaluronic acid,polyethylene glycols; and (g) surfactants including fluorinated andnonfluorinated compounds such as saturated and unsaturated lipids,nonionic detergents, nonionic block copolymers, ionic surfactants andcombinations thereof. In particular embodiments, suspending particlesmay include a calcium salt, such as calcium chloride, as described, forexample, in U.S. Pat. No. 7,442,388.

Additionally, phospholipids from both natural and synthetic sources maybe used in preparing suspending particles suitable for use in thecompositions described herein. In particular embodiments, thephospholipid chosen will have a gel to liquid crystal phase transitionof greater than about 40° C. Exemplary phospholipids are relatively longchain (i.e., C₁₆-C₂₂) saturated lipids and may comprise saturatedphospholipids, such as saturated phosphatidylcholines having acyl chainlengths of 16 C or 18 C (palmitoyl and stearoyl). Exemplaryphospholipids include phosphoglycerides such asdipalmitoylphosphatidylcholine, disteroylphosphatidylcholine,diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine,diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chainsaturated phosphatidylethanolamines, long-chain saturatedphosphatidylserines, long-chain saturated phosphatidylglycerols, andlong-chain saturated phosphatidylinositols. Additional excipients aredisclosed in International Patent Publication No. WO 96/32149 and U.S.Pat. Nos. 6,358,530, 6,372,258 and 6,518,239.

In particular embodiments, the suspending particles may be formed usingone or more lipids, phospholipids or saccharides, as described herein.In some embodiments, suspending particles include one or moresurfactants. The use of suspending particles formed of or incorporatingone or more surfactants may promote absorption of the selected activeagent, thereby increasing bioavailability. The suspending particlesdescribed herein, such as, for example, suspending particles formedusing one or more lipids, can be formed to exhibit a desired surfacerugosity (roughness), which can further reduce inter-particleinteractions and improve aerosolization by reducing the surface areaavailable for particle-particle interaction. In further embodiments, ifsuitable, a lipid that is naturally occurring in the lung could be usedin forming the suspending particles, as such suspending particles thathave the potential to reduce opsonization (and thereby reducingphagocytosis by alveolar macrophages), thus providing a longer-livedcontrolled release particle in the lung.

In another aspect, the suspending particles utilized in the compositionsdescribed herein may be selected to increase storage stability of theselected active agent, similar to that disclosed in International PatentPublication No WO 2005/000267. For example, in one embodiment, thesuspending particles my include pharmaceutically acceptable glassstabilization excipients having a Tg of at least 55° C., at least 75°C., or at least 100° C. Glass formers suitable for use in compositionsdescribed herein include, but are not limited to, one or more oftrileucine, sodium citrate, sodium phosphate, ascorbic acid, inulin,cyclodextrin, polyvinyl pyrrolidone, mannitol, sucrose, trehalose,lactose, and, proline. Examples of additional glass-forming excipientsare disclosed in U.S. Pat. Nos. RE 37,872, 5,928,469, 6,258,341, and6,309,671.

The suspending particles may be designed, sized and shaped as desired toprovide desirable stability and active agent delivery characteristics.In one exemplary embodiment, the suspending particles compriseperforated microstructures as described herein. Where perforatedmicrostructures are used as suspending particles in the compositionsdescribed herein, they may be formed using one or more excipients asdescribed herein. For example, in particular embodiments, perforatedmicrostructures may include at least one of the following: lipids,phospholipids, nonionic detergents, nonionic block copolymers, ionicsurfactants, biocompatible fluorinated surfactants and combinationsthereof, particularly those approved for pulmonary use. Specificsurfactants that may be used in the preparation of perforatedmicrostructures include poloxamer 188, poloxamer 407 and poloxamer 338.Other specific surfactants include oleic acid or its alkali salts. Inone embodiment, the perforated microstructures include greater thanabout 10% w/w surfactant.

In some embodiments, suspending particles may be prepared by forming anoil-in-water emulsion, using a fluorocarbon oil (e.g., perfluorooctylbromide, perfluorodecalin) which may be emulsified using a surfactantsuch as a long chain saturated phospholipid. The resultingperfluorocarbon in water emulsion may be then processed using a highpressure homogenizer to reduce the oil droplet size. The perfluorocarbonemulsion may be fed into a spray dryer, optionally with an active agentsolution, if it is desirable to include active agent within the matrixof the perforated microstructures. As is well known, spray drying is aone-step process that converts a liquid feed to a dried particulateform. Spray drying has been used to provide powdered pharmaceuticalmaterial for various administrative routes, including inhalation.Operating conditions of the spray dryer (such as inlet and outlettemperature, feed rate, atomization pressure, flow rate of the dryingair and nozzle configuration) can be adjusted to produce the desiredparticle size producing a yield of the resulting dry microstructures.Such methods of producing exemplary perforated microstructures aredisclosed in U.S. Pat. No. 6,309,623 to Weers et al.

Perforated microstructures as described herein may also be formedthrough lyophilization and subsequent milling or micronization.Lyophilization is a freeze-drying process in which water is sublimedfrom the composition after it is frozen. This process allows dryingwithout elevated temperatures. In yet further embodiments, thesuspending particles may be produced using a spray freeze dryingprocess, such as is disclosed in U.S. Pat. No. 5,727,333.

Furthermore, suspending particles as described herein may includebulking agents, such as polymeric particles. Polymeric polymers may beformed from biocompatible and/or biodegradable polymers, copolymers orblends. In one embodiment, polymers capable of forming aerodynamicallylight particles may be used, such as functionalized polyester graftcopolymers and biodegradable polyanhydrides. For example, bulk erodingpolymers based on polyesters including poly(hydroxy acids) can be used.Polyglycolic acid (PGA), polyactic acid (PLA) or copolymers thereof maybe used to form suspending particles. The polyester may include acharged or functionalizable group, such as an amino acid. For example,suspending particles may be formed of poly(D,L-lactic acid) and/orpoly(D,L-lactic-co-glycolic acid) (PLGA), which incorporate a surfactantsuch as DPPC.

Other potential polymer candidates for use in suspending particles mayinclude polyamides, polycarbonates, polyalkylenes such as polyethylene,polypropylene, poly(ethylene glycol), poly(ethylene oxide),poly(ethylene terephthalate), poly vinyl compounds such as polyvinylalcohols, polyvinyl ethers, and polyvinyl esters, polymers of acrylicand methacrylic acids, celluloses and other polysaccharides, andpeptides or proteins, or copolymers or blends thereof. Polymers may beselected with or modified to have the appropriate stability anddegradation rates in vivo for different controlled drug deliveryapplications.

The compositions described herein may include two or more species ofsuspending particles. Even further, compositions according to thepresent description can include suspending particles that include one ormore active agents incorporated into the suspending particles. Whereactive agent is incorporated into suspending particles, the suspendingparticles will be of a respirable size and can be formulated andproduced using, for example, the methods and materials described herein.

Compositions formulated according to the present teachings can inhibitdegradation of active agent included therein. For example, in specificembodiments, the compositions described herein inhibit one or more offlocculation, aggregation and the solution mediated transformation ofactive agent material included in the compositions. The pharmaceuticalcompositions described herein are suited for respiratory delivery viaand MDI in a manner that achieves desirable delivered dose uniformity(“DDU”) of each active agent included in a combination of two or moreactive agents, even with combinations including potent and highly potentactives. As is illustrated in detail in the Examples included herein,even when delivering very low doses of two or more active agents,compositions described herein can achieve a DDU of ±30%, or better, foreach active agent throughout emptying of an MDI canister. In one suchembodiment, compositions described herein achieve a DDU of ±25%, orbetter, for each active agent throughout emptying of an MDI canister. Inyet another such embodiment, compositions described herein achieve a DDUfor the active agent of ±20%, or better, for each active agentthroughout emptying of an MDI canister.

Pharmaceutical compositions described herein also serve to substantiallypreserve FPF and FPD performance throughout emptying of an MDI canister,even after being subjected to accelerated degradation conditions. Forinstance, compositions according to the present description maintain asmuch as 80%, 90%, 95%, or more, of the original FPF and FPD performancethroughout emptying of an MDI canister, even after being subjected toaccelerated degradation conditions. Compositions described hereinprovide the added benefit of achieving such performance while beingformulated using non-CFC propellants and eliminating or substantiallyavoiding pharmaceutical effects often experienced with compositionsincorporating multiple active agents. In specific embodiments, thecompositions described herein achieve desired one or all of a targetedDDU, FPF and FPD performance while being formulated with suspensionmedium including only one or more non-CFC propellants and without theneed to modify the characteristics of the non-CFC propellant, such as bythe addition of, for example, one or more cosolvent, antisolvent,solubilizing agent, adjuvant or other propellant modifying material.

In one embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingglycopyrrolate, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of glycopyrrolateof between about 15 μg and about 80 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures exhibiting a volume median optical diameterof between about 1.5 μm and about 10 μm, wherein the first and secondspecies of active agent particles associate with the plurality ofsuspending particles to form a co-suspension. In one such embodiment,the ratio of the total mass of the suspending particles to the totalmass of the first and second species of active agent particles isselected from between about 3:1 and about 15:1 and between about 2:1 and8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingtiotropium, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of tiotropium ofbetween about 5 μg and about 20 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures exhibiting a volume median optical diameterof between about 1.5 μm and about 10 μm, wherein the first and secondspecies of active agent particles associate with the plurality ofsuspending particles to form a co-suspension. In one such embodiment,the ratio of the total mass of the suspending particles to the totalmass of the first and second species of active agent particles isselected from between about 3:1 and about 15:1 and between about 2:1 and8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a plurality of active agent particles comprisingglycopyrrolate, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of glycopyrrolateof between about 15 μg and about 80 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, wherein the plurality of suspendingparticles exhibit a volume median optical diameter of between about 1.5μm and about 10 μm, are included in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler, and associate with the plurality of active agent particles toform a co-suspension. In one such embodiment, the ratio of the totalmass of the suspending particles to the total mass of the first andsecond species of active agent particles is selected from between about3:1 and about 15:1 and between about 2:1 and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a plurality of active agent particles comprisingtiotropium, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of tiotropium ofbetween about 5 μg and about 20 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, wherein the plurality of suspendingparticles exhibit a volume median optical diameter of between about 1.5μm and about 10 μm, are included in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler, and associate with the plurality of active agent particles toform a co-suspension. In one such embodiment, the ratio of the totalmass of the suspending particles to the total mass of the first andsecond species of active agent particles is selected from between about3:1 and about 15:1 and between about 2:1 and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingglycopyrrolate, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of glycopyrrolateof between about 15 μg and about 80 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; a third species of active agent particles comprising acorticosteroid selected from beclomethasone, budesonide, ciclesonide,flunisolide, fluticasone, methyl-prednisolone, mometasone, prednisoneand trimacinolone, including any pharmaceutically acceptable salts,esters, isomers or solvates thereof; and a plurality of respirablesuspending particles comprising perforated microstructures exhibiting avolume median optical diameter of between about 1.5 μm and about 10 μm,wherein the first, second and third species of active agent particlesassociate with the plurality of suspending particles to form aco-suspension. In one such embodiment, at least 90% of the first,second, and third species of active agent particles by volume exhibit anoptical diameter of less than 7 μm, and the ratio of the total mass ofthe suspending particles to the total mass of the first, second, andthird species of active agent particles is selected from between about3:1 and about 15:1 and between about 2:1 and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingglycopyrrolate, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of glycopyrrolateof between about 15 μg and about 80 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; a third species of active agent particles comprisingbudesonide, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of budesonide ofbetween about 30 μg and about 50 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures exhibiting a volume median optical diameterof between about 1.5 μm and about 10 μm, wherein the first, second andthird species of active agent particles associate with the plurality ofsuspending particles to form a co-suspension. In one such embodiment, atleast 90% of the first, second, and third species of active agentparticles by volume exhibit an optical diameter of less than 7 μm, andthe ratio of the total mass of the suspending particles to the totalmass of the first, second, and third species of active agent particlesis selected from between about 3:1 and about 15:1 and between about 2:1and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingtiotropium, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of tiotropium ofbetween about 5 μg and about 20 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; a third species of active agent particles comprisingbudesonide, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of budesonide ofbetween about 30 μg and about 50 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures exhibiting a volume median optical diameterof between about 1.5 μm and about 10 μm, wherein the first, second andthird species of active agent particles associate with the plurality ofsuspending particles to form a co-suspension. In one such embodiment, atleast 90% of the first, second, and third species of active agentparticles by volume exhibit an optical diameter of less than 7 μm, andthe ratio of the total mass of the suspending particles to the totalmass of the first, second, and third species of active agent particlesis selected from between about 3:1 and about 15:1 and between about 2:1and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingglycopyrrolate, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of glycopyrrolateof between about 15 μg and about 80 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; a third species of active agent particles comprisingmometasone, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of mometasone ofbetween about 20 μg and about 100 per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures exhibiting a volume median optical diameterof between about 1.5 μm and about 10 μm, wherein the first, second andthird species of active agent particles associate with the plurality ofsuspending particles to form a co-suspension. In one such embodiment, atleast 90% of the first, second, and third species of active agentparticles by volume exhibit an optical diameter of less 7 μm, and theratio of the total mass of the suspending particles to the total mass ofthe first, second, and third species of active agent particles isselected from between about 3:1 and about 15:1 and between about 2:1 and8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingtiotropium, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of tiotropium ofbetween about 5 μg and about 20 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; a third species of active agent particles comprisingmometasone, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of mometasone ofbetween about 20 μg and about 100 per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures exhibiting a volume median optical diameterof between about 1.5 μm and about 10 μm, wherein the first, second andthird species of active agent particles associate with the plurality ofsuspending particles to form a co-suspension. In one such embodiment, atleast 90% of the first, second, and third species of agent particles byvolume exhibit an optical diameter of less than 7 μm, and the ratio ofthe total mass of the suspending particles to the total mass of thefirst, second, and third species of active agent particles is selectedfrom between about 3:1 and about 15:1 and between about 2:1 and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingglycopyrrolate, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of glycopyrrolateof between about 15 μg and about 80 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures incorporating a corticosteroid selected frombeclomethasone, budesonide, ciclesonide, flunisolide, fluticasone,methyl-prednisolone, mometasone, prednisone and trimacinolone, includingany pharmaceutically acceptable salts, esters, isomers or solvatesthereof, wherein the suspending particles exhibit a volume medianoptical diameter of between about 1.5 μm and about 10 μm and associatewith the first and second species of active agent particles to form aco-suspension. In one such embodiment, at least 90% of the first andsecond species of active agent particles by volume exhibit an opticaldiameter of less than 7 μm, and the ratio of the total mass of thesuspending particles to the total mass of the first and second speciesof active agent particles is selected from between about 3:1 and about15:1 and between about 2:1 and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingglycopyrrolate, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of glycopyrrolateof between about 15 μg and about 80 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures incorporating budesonide, including anypharmaceutically acceptable salts, esters, isomers or solvates thereof,wherein the suspending particles include sufficient budesonide toprovide a delivered dose of budesonide of between about 30 μg and about50 μg per actuation of the metered dose inhaler, exhibit a volume medianoptical diameter of between about 1.5 μm and about 10 μm, and associatewith the first and second species of active agent particles to form aco-suspension. In one such embodiment, at least 90% of the first andsecond species of active agent particles by volume exhibit an opticaldiameter of less than 7 μm, and the ratio of the total mass of thesuspending particles to the total mass of the first and second speciesof active agent particles is selected from between about 3:1 and about15:1 and between about 2:1 and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingglycopyrrolate, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of glycopyrrolateof between about 15 μg and about 80 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures incorporating mometasone, including anypharmaceutically acceptable salts, esters, isomers or solvates thereof,wherein the suspending particles include sufficient mometasone toprovide a delivered dose of mometasone of between about 20 μg and about100 μg per actuation of the metered dose inhaler, exhibit a volumemedian optical diameter of between about 1.5 μm and about 10 μm, andassociate with the first and second species of active agent particles toform a co-suspension. In one such embodiment, at least 90% of the firstand second species of active agent particles by volume exhibit anoptical diameter of less than 7 μm, and the ratio of the total mass ofthe suspending particles to the total mass of the first and secondspecies of active agent particles is selected from between about 3:1 andabout 15:1 and between about 2:1 and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingtiotropium, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of tiotropium ofbetween about 5 μg and about 20 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures incorporating a corticosteroid selected frombeclomethasone, budesonide, ciclesonide, flunisolide, fluticasone,methyl-prednisolone, mometasone, prednisone and trimacinolone, includingany pharmaceutically acceptable salts, esters, isomers or solvatesthereof, wherein the suspending particles exhibit a volume medianoptical diameter of between about 1.5 μm and about 10 μm and associatewith the first and second species of active agent particles to form aco-suspension. In one such embodiment, at least 90% of the first andsecond species of active agent particles by volume exhibit an opticaldiameter of less than 7 μm, and the ratio of the total mass of thesuspending particles to the total mass of the first and second speciesof active agent particles is selected from between about 3:1 and about15:1 and between about 2:1 and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingtiotropium, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of tiotropium ofbetween about 5 μg and about 20 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures incorporating budesonide, including anypharmaceutically acceptable salts, esters, isomers or solvates thereof,wherein the suspending particles include sufficient budesonide toprovide a delivered dose of budesonide of between about 30 μg and about50 μg per actuation of the metered dose inhaler, exhibit a volume medianoptical diameter of between about 1.5 μm and about 10 μm, and associatewith the first and second species of active agent particles to form aco-suspension. In one such embodiment, at least 90% of the first andsecond species of active agent particles by volume exhibit an opticaldiameter of less than 7 μm, and the ratio of the total mass of thesuspending particles to the total mass of the first and second speciesof active agent particles is selected from between about 3:1 and about15:1 and between about 2:1 and 8:1.

In another embodiment, a co-suspension composition deliverable from ametered dose inhaler according to the present description includes thefollowing: a suspension medium comprising a pharmaceutically acceptableHFA propellant; a first species of active agent particles comprisingtiotropium, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of tiotropium ofbetween about 5 μg and about 20 μg per actuation of the metered doseinhaler; a second species of active agent particles comprisingformoterol, including any pharmaceutically acceptable salts, esters,isomers or solvates thereof, suspended in the suspension medium at aconcentration sufficient to provide a delivered dose of formoterol ofbetween about 2 μg and about 10 μg per actuation of the metered doseinhaler; and a plurality of respirable suspending particles comprisingperforated microstructures incorporating mometasone, including anypharmaceutically acceptable salts, esters, isomers or solvates thereof,wherein the suspending particles include sufficient mometasone toprovide a delivered dose of mometasone of between about 20 μg and about100 μg per actuation of the metered dose inhaler, exhibit a volumemedian optical diameter of between about 1.5 μm and about 10 μm, andassociate with the first and second species of active agent particles toform a co-suspension. In one such embodiment, at least 90% of the firstand second species of active agent particles by volume exhibit anoptical diameter of less than 7 μm, and the ratio of the total mass ofthe suspending particles to the total mass of the first and secondspecies of active agent particles is selected from between about 3:1 andabout 15:1 and between about 2:1 and 8:1.

III. Metered Dose Inhaler Systems

As described in relation to the methods provided herein, theco-suspension compositions disclosed herein may be used in an MDIsystem. MDIs are configured to deliver a specific amount of a medicamentin aerosol form. In one embodiment, an MDI system includes apressurized, liquid phase formulation-filled canister disposed in anactuator formed with a mouthpiece. The MDI system may include theformulations described herein, which include a suspension medium, atleast one species of active agent particles and at least one species ofsuspending particles. The canister used in the MDI may be of anysuitable configuration, and in one exemplary embodiment, the canistermay have a volume ranging from about 5 mL to about 25 mL, such as, forexample a canister having a 19 mL volume. After shaking the device, themouthpiece is inserted into a patient's mouth between the lips andteeth. The patient typically exhales deeply to empty the lungs and thentakes a slow deep breath while actuating the cartridge.

Inside an exemplary cartridge is a metering valve including a meteringchamber capable of holding a defined volume of the formulation (e.g., 63μl or any other suitable volume available in commercially availablemetering valves), which is released into an expansion chamber at thedistal end of the valve stem when actuated. The actuator retains thecanister and may also include a port with an actuator nozzle forreceiving the valve stem of the metering valve. When actuated, thespecified volume of formulation travels to the expansion chamber, outthe actuator nozzle and into a high-velocity spray that is drawn intothe lungs of a patient.

IV. Methods

Methods of formulating a pharmaceutical composition for respiratorydelivery of at least two active agents are provided herein. In oneembodiment, the method involves the steps of providing a suspensionmedium, one or more species of active agent particles and one or morespecies of suspending particles, and combining such constituents to forma composition wherein the active agent particles associate with thesuspending particles and co-locate with the suspending particles withinthe suspension medium such that a co-suspension as described herein isformed. In one such embodiment, the association of the active agentparticles and the suspending particles is such that they do not separatedue to their different buoyancies in a propellant. As will beappreciated, a method of formulating a pharmaceutical composition asdescribed herein can include providing two or more species of activeagent particles in combination with one or more species of suspendingparticles. In further embodiments, the method may include providing twoor more species of suspending particles in combination with two or morespecies of active agent particles in a manner which results in aco-suspension. In still other embodiments, one or more species of activeagent particles may be combined with one or more species of suspendingparticles, as described herein. In particular embodiments, the activeagent material included in the active agent particles is selected fromone or more of LABA, LAMA or corticosteroid active agents. In certainembodiments, the active agent particles consist essentially of activeagent material, and are free of additional excipients, adjuvants,stabilizers, etc.

In specific embodiments of methods for providing a stabilizedcomposition of a combination of two or more active agents, the presentdisclosure provides methods for inhibiting the solution mediatedtransformation of the active agents in a pharmaceutical composition forpulmonary delivery. In one embodiment, a suspension medium as describedherein, such as a suspension medium formed by an HFA propellant, isobtained. Suspending particles are also obtained or prepared asdescribed herein. Active agent particles are also obtained, and thesuspension medium, suspending particles and active agent particles arecombined to form a co-suspension wherein the active agent particlesassociate with suspending particles and co-locate with the suspendingparticles within the continuous phase formed by the suspension medium.When compared to active agent particles contained in the same suspensionmedium in the absence of suspending particles, co-suspensions accordingto the present description have been found to exhibit a higher toleranceto solution mediated phase transformation that leads to irreversiblecrystal aggregation, and thus may lead to improved stability and dosinguniformity.

In further embodiments, methods for forming stabilized compositionsincluding two or more active agents for pulmonary delivery includepreserving the FPF and/or FPD of the composition throughout emptying ofan MDI canister. In specific embodiments of methods for preserving theFPF and/or FPD provided by a pharmaceutical composition for pulmonarydelivery, a respirable co-suspension as described herein is providedwhich is capable of maintaining the FPD and/or the FPF to within ±20%,±10%, or even ±5% the initial FPD and/or FPF, respectively, throughoutemptying of an MDI canister. Such performance can be achieved where twoor more active agents are incorporated into the co-suspension and evenafter the co-suspension is subjected to accelerated degradationconditions. In one embodiment, a suspension medium as described herein,such as a suspension medium formed by an HFA propellant, is obtained.Suspending particles are also obtained or prepared as described herein.Active agent particles are also obtained, and the suspension medium,suspending particles and active agent particles are combined to form aco-suspension wherein the active agent particles associate withsuspending particles and co-locate with the suspending particles withinthe suspension medium. Even after exposure of such composition to one ormore temperature cycling events, the co-suspension maintains an FPD orFPF within ±20%, ±10%, or even ±5% of the respective values measuredprior to exposure of the composition to multiple temperature cyclingevents.

Methods for preparing an MDI for respiratory delivery of two or moreactive agents are disclosed. In certain embodiments, such a method mayinclude loading a canister, as described herein, with active agentparticles and suspending particles. An actuator valve can be attached toan end of the canister and the canister sealed. The actuator valve maybe adapted for dispensing a metered amount of the active agents includedin the co-suspension composition per actuation of the MDI. The canistercan be charged with a pharmaceutically acceptable suspension medium,such as a propellant as described herein, whereupon the active agentparticles and suspending particles yield a stable co-suspension in thesuspension medium.

In methods involving respiratory delivery of two or more active agentsusing compositions described herein, the compositions may be deliveredby an MDI. Therefore, in particular embodiments of such methods, an MDIloaded with a composition described herein is obtained, and two or moreactive agents are administered to a patient via respiratory deliverythrough actuation of the MDI. For example, in one embodiment involvingpulmonary delivery of two or more active agents, after shaking the MDIdevice, the mouthpiece is inserted into a patient's mouth between thelips and teeth. The patient typically exhales deeply to empty the lungsand then takes a slow deep breath while actuating the cartridge of theMDI. When actuated, the specified volume of formulation travels to theexpansion chamber, out the actuator nozzle and into a high-velocityspray that is drawn into the lungs of a patient. In one embodiment thedose of each active agent delivered throughout emptying of an MDIcanister is not more than 30% greater than the mean delivered dose andis not less than 30% less than the mean delivered dose. Therefore,methods of achieving a desired DDU of two or more active agentsdelivered from an MDI are also provided. In such embodiments, the methodmay include achieving a DDU for each of the two or more active agentsdelivered from an MDI selected from, for example, a DDU of ±30%, orbetter, a DDU of ±25%, or better, and a DDU of ±20%, or betterthroughout emptying of the MDI canister from which the co-suspensioncomposition is delivered.

Methods for treating patients suffering from an inflammatory orobstructive pulmonary disease or condition are provided herein. Inspecific embodiments, such methods include pulmonary delivery of apharmaceutical composition described herein, and in certain suchembodiments, pulmonary administration of the pharmaceutical compositionis accomplished by delivering the composition using an MDI. The diseaseor condition to be treated can be selected from any inflammatory orobstructive pulmonary disease or condition that responds to theadministration of, for example, the active agents described herein. Insome embodiments, the combination of active agents includes at least oneactive agent selected from LAMA, LABA or corticosteroid active agents.In particular embodiments, the pharmaceutical compositions describedherein may be used in treating a disease or disorder selected fromasthma, COPD, exacerbation of airways hyper reactivity consequent toother drug therapy, allergic rhinitis, sinusitis, pulmonaryvasoconstriction, inflammation, allergies, impeded respiration,respiratory distress syndrome, pulmonary hypertension, pulmonaryvasoconstriction, emphysema, and any other respiratory disease,condition, trait, genotype or phenotype that can respond to theadministration of combinations of active agents described herein. Incertain embodiments, the pharmaceutical compositions described hereinmay be used in treating pulmonary inflammation and obstructionassociated with cystic fibrosis.

Additionally, pharmaceutical compositions according to the presentdescription delivered from an MDI provide desirable pharmacodynamic (PD)performance. In particular embodiments, pulmonary delivery of thepharmaceutical compositions described herein results in rapid,significant improvement in the lung capacity, which can be characterizedby an improvement in the patient's forced expiratory volume in onesecond (FEV₁). For example, in particular embodiments, methods forachieving a clinically significant increase in FEV₁ are provided,wherein such methods include providing a co-suspension compositioncomprising two or more active agents, wherein at least one of thoseactive agents is selected from a LABA, LAMA or corticosteroid activeagents, as described herein, and administering such composition to apatient experiencing pulmonary inflammation or obstruction via an MDI.In one such embodiment, the active agents included in the compositioninclude a combination selected from one of a combination of LABA andLAMA active agents, a combination of LABA and corticosteroid activeagents, a combination of LAMA and corticosteroid active agents, and acombination of LABA, LAMA and corticosteroid active agents. For purposesof the present disclosure, a clinically significant increase in FEV₁ isany increase of 100 ml or greater, and in certain embodiments of themethods described herein, administration of compositions according tothe present description to patient results in a clinically significantincrease in FEV₁ within 1 hour or less. In other such embodiments,methods for administering a composition as described herein to a patientvia an MDI result in a clinically significant increase in FEV1 within0.5 hours or less.

In further embodiments, methods are provided for achieving an increasein FEV₁ greater than 100 ml. For example, in certain embodiments, themethods described herein include methods for achieving an FEV₁ of 150 mlor greater within a period of time selected from 0.5 hours or less, 1hour or less, and 1.5 hours or less. In other embodiments, the methodsdescribed herein include methods for achieving an FEV₁ of 200 ml orgreater within a period of time selected from 0.5 hours or less, 1 houror less, and 1.5 hours or less, and 2 hours or less. In yet other suchembodiments, the methods described herein include methods for achievingan FEV₁ of 250 ml or greater within a period of time selected from 0.5hours or less, 1 hour or less, and 1.5 hours or less, and 2 hours orless. In still other such embodiments, the methods described hereininclude methods for achieving an FEV₁ of 300 ml or greater within aperiod of time selected from 0.5 hours or less, 1 hour or less, and 1.5hours or less, and 2 hours or less. In yet other such embodiments, themethods described herein include methods for achieving an FEV₁ of 350 mlor greater within a period of time selected from 0.5 hours or less, 1hour or less, and 1.5 hours or less, and 2 hours or less. In certainsuch embodiments, the active agents included in the composition includea combination selected from one of a combination of LABA and LAMA activeagents, a combination of LABA and corticosteroid active agents, acombination of LAMA and corticosteroid active agents, and a combinationof LABA, LAMA and corticosteroid active agents, wherein the compositionis delivered to the patient via an MDI.

In still further embodiments, methods for achieving and maintaining aclinically significant increase in FEV₁ are provided. In particularembodiments, upon administration of a single dose of a combination ofactive agents formulated in a composition as described herein to apatient via an MDI, a clinically significant increase in FEV₁ isachieved in a period of time selected from 0.5 hours or less, 1 hour orless, and 1.5 hours or less, and the clinically significant increase inFEV₁ is maintained for up 12 hours or more. In certain such embodiments,the increase in FEV₁ may be selected from an increase of 150 ml orgreater, 200 ml or greater, 250 ml or greater, 300 ml or greater, and350 ml or greater, and the increase in FEV₁ remains clinicallysignificant for a time period selected from up to 4 hours, up to 6hours, up to 8 hours, up to 10 hours, and up to 12 hours, or more. Incertain such embodiments, the active agents included in the compositioninclude a combination selected from one of a combination of LABA andLAMA active agents, a combination of LABA and corticosteroid activeagents, a combination of LAMA and corticosteroid active agents, and acombination of LABA, LAMA and corticosteroid active agents, wherein thecomposition is delivered to the patient via an MDI.

Compositions, systems and methods described herein are not only suitedto achieving desirable pharmacodynamic performance in short periods oftime, but will achieve such results in a high percentage of patients.For example, methods are provided herein for achieving a 10% or greaterincrease in FEV₁ in 50% or more of patients experiencing pulmonaryinflammation or obstruction. For example, in particular embodiments,methods for achieving a 10% or greater increase in FEV₁ in a patientinclude providing a co-suspension composition comprising a combinationof active agents, wherein at least one active agent is selected fromLABA, LAMA, and corticosteroid active agents as described herein, andadministering such composition via an MDI to a patient experiencingpulmonary inflammation or obstruction. In certain such embodiments,administration of the composition results in 10% or greater increase inFEV₁ within a period of time selected from 0.5 hours or less, 1 hour orless, 1.5 hours or less, and 2 hours in 50% or more of patients. Inother such embodiments, administration of the composition results in 10%or greater increase in FEV₁ within a period of time selected from 0.5hours or less, 1 hour or less, 1.5 hours or less, and 2 or less hours in60% or more of patients. In still other such embodiments, administrationof the composition results in 10% or greater increase in FEV₁ within aperiod of time selected from 0.5 hours or less, 1 hour or less, 1.5hours or less, and 2 hours or less in 70% or more of patients. In yetother such embodiments, administration of the composition results in 10%or greater increase in FEV₁ within a period of time selected from 0.5hours or less, 1 hour or less, 1.5 hours or less, and 2 or less hours in80% or more of patients. In certain such embodiments, the active agentsincluded in the composition include a combination selected from one of acombination of LABA and LAMA active agents, a combination of LABA andcorticosteroid active agents, a combination of LAMA and corticosteroidactive agents, and a combination of LABA, LAMA and corticosteroid activeagents, wherein the composition is delivered to the patient via an MDI.

In specific embodiments, the methods described herein facilitatetreatment of patients experiencing pulmonary inflammation orobstruction, wherein such methods include providing a co-suspensioncomposition comprising a combination of active agents as describedherein and administering such composition to a patient experiencingpulmonary inflammation or obstruction via an MDI, and administration ofthe composition via an MDI results in patients experiencing either anincrease from baseline in FEV₁ of at least 200 ml or a 12%, or greater,increase from baseline in FEV₁ coupled with total increase in FEV₁ of atleast 150 ml. In certain such embodiments, administration of thecomposition results in either an increase from baseline in FEV₁ of atleast 200 ml or a 12%, or greater, increase from baseline in FEV₁coupled with total increase in FEV₁ of at least 150 ml within a periodof time selected from 1 hour, or less, 1.5 hours or less, 2 hours, orless, and 2.5 hours, or less, in 50% or more of patients. In other suchembodiments, administration of the composition results in an increasefrom baseline in FEV₁ of at least 200 ml or a 12%, or greater, increasefrom baseline in FEV₁ coupled with total increase in FEV₁ of at least150 ml within a period of time selected from 1 hour, or less, 1.5 hours,or less, 2 hours, or less, and 2.5 hours, or less, in 60% or more ofpatients. In still other such embodiments, administration of thecomposition results in either an increase from baseline in FEV₁ of atleast 200 ml or a 12%, or greater, increase from baseline in FEV₁coupled with total increase in FEV₁ of at least 150 ml within a periodof time selected from 1.5 hours, or less, 2 hours, or less, 2.5 hours,or less, and 3 hours, or less, in 70% or more of patients. In yet othersuch embodiments, administration of the composition results in either anincrease from baseline in FEV₁ of at least 200 ml or a 12%, or greater,increase from baseline in FEV₁ coupled with total increase in FEV₁ of atleast 150 ml within a period of time selected from 1.5 hours, or less, 2hours, or less, 2.5 hours or less, and 3 hours, or less, in 80% or moreof patients. In certain such embodiments, the active agents included inthe composition include a combination selected from one of a combinationof LABA and LAMA active agents, a combination of LABA and corticosteroidactive agents, a combination of LAMA and corticosteroid active agents,and a combination of LABA, LAMA and corticosteroid active agents,wherein the composition is delivered to the patient via an MDI.

In some embodiments, the methods for achieving and maintaining aclinically significant increase in FEV₁ described herein result in anincrease in FEV₁ that represents a significant improvement in FEV₁relative to the improvement provided by compositions delivering only asingle active agent. For purposes of comparing the FEV₁ performance of acomposition described herein with one delivering only a single activeagent, a significant improvement in FEV₁ is an improvement of 60 ml orgreater. For example, in particular embodiments, methods for achieving asignificant improvement in FEV₁ relative to the improvement provided bycompositions delivering only a single active agent include providing aco-suspension composition as described herein comprising a combinationof active agents, wherein at least one active agent is selected fromLABA, LAMA, and corticosteroid active agents as described herein, andadministering such composition via an MDI to a patient experiencingpulmonary inflammation or obstruction. In certain such embodiments,administration of the co-suspension composition results in animprovement in FEV₁ AUC₀₋₁₂ of at least 70 ml when compared to the FEV₁AUC₀₋₁₂ achieved by a composition delivering a single active agent. Inother such embodiments, administration of the co-suspension compositionresults in an improvement in FEV₁ AUC₀₋₁₂ of at least 80 ml whencompared to the FEV₁ AUC₀₋₁₂ achieved by a composition delivering asingle active agent. In still other embodiments, administration of theco-suspension composition results in an improvement in FEV₁ AUC₀₋₁₂ ofat least 90 ml when compared to the FEV₁ AUC₀₋₁₂ achieved by acomposition delivering a single active agent.

In other embodiments, methods for achieving a significant improvement inFEV₁ relative to the improvement provided by compositions deliveringonly a single active agent include providing a co-suspension compositionas described herein comprising a combination of active agents, whereinat least one active agent is selected from LABA, LAMA, andcorticosteroid active agents as described herein, administering suchcomposition via an MDI to a patient experiencing pulmonary inflammationor obstruction, with such administration resulting in a significantimprovement in the peak change in FEV₁ (Peak FEV₁) when compared to thePeak FEV₁ achieved by a composition delivering a single active agent. Incertain such embodiments, administration of the co-suspensioncomposition as described herein results in an improvement in Peak FEV₁of at least 70 ml when compared to the Peak FEV₁ achieved by acomposition delivering a single active agent. In other such embodiments,administration of the co-suspension composition as described hereinresults in an improvement in Peak FEV₁ of at least 80 ml when comparedto the Peak FEV₁ achieved by a composition delivering a single activeagent. In further such embodiments, administration of the co-suspensioncomposition as described herein results in an improvement in Peak FEV₁of at least 90 ml when compared to the Peak FEV₁ achieved by acomposition delivering a single active agent.

Methods for providing a clinically significant increase in inspiratorycapacity (IC) in patients suffering from pulmonary inflammation orobstruction are also provided. As used herein, IC is defined as themaximal volume of gas that can be taken into the lungs in a fullinhalation following a normal expiration, and a clinically significantincrease in IC is any increase of 70 ml or greater. For example, inparticular embodiments, methods for improving IC as described hereininclude providing a co-suspension composition as described hereincomprising a combination of active agents, wherein at least one activeagent is selected from LABA, LAMA, and corticosteroid active agents asdescribed herein, and administering such composition via an MDI to apatient experiencing pulmonary inflammation or obstruction, whereinadministration of the composition results in an increase in IC of 70 mlor greater. In certain such embodiments, administration of thecomposition according to the present description results in an increasein IC of 100 ml or greater. In other such embodiments, administration ofthe composition according to the present description results in anincrease in IC of 200 ml or greater. In still other such embodiments,administration of composition according to the present descriptionresults in an increase in IC of 300 ml or greater, and in still otherembodiments, administration of composition according to the presentdescription results in an increase in IC of 350 ml or greater. Inspecific such embodiments, the increase in IC is experienced rapidly.For example, in each of the methods described, a clinically significantincrease in IC or an increase in IC selected from 100 ml or greater, 200ml or greater, 300 ml or greater, or 350 ml or greater can beexperienced in a patient within a time selected from 1 hour or less and2 hours or less.

The methods for increasing IC described herein are not only useful forquickly achieving clinically significant increases in IC in a shortperiod of time, but they are useful for maintaining a clinicallysignificant increase in IC over time. For example, as is highlighted bythe clinical results presented in Example 12, the clinically significantincreases in IC provided by the methods described herein are experiencedby patients quickly after administration, the increases in IC remainclinically significant for a period of up to 12 hours or morepost-administration, and the increases in IC remain clinicallysignificant even after chronic dosing (e.g., multiple consecutive dosingdays).

Additionally, compositions according to the present description provideincreases in IC that are significantly greater than increases in ICprovided by compositions delivering only a single active agent. Inembodiments of the methods described herein for increasing IC,administration of a co-suspension composition as described hereinprovides an increase in IC that is at least 70 ml greater than theincrease in IC provided by a composition delivering only a single activeagent. In one such embodiment, the increase in IC provided byadministering a co-suspension composition described herein is at least100 ml greater than the increase in IC provided by a compositiondelivering only a single active agent. In another such embodiment, theincrease in IC provided by administering a co-suspension compositiondescribed herein is at least 125 ml greater than the increase in ICprovided by a composition delivering only a single active agent

In some embodiments, the methods described herein for achieving desiredpharmacodynamic effects are characterized by delivery of relatively lowamounts of active agents. In certain such embodiments, for example, themethods described herein for achieving clinically significant increasesin FEV₁ include administering a co-suspension as described hereincomprising a combination of glycopyrrolate and formoterol active agents,wherein the co-suspension is administered to a patient via a metereddose inhaler up to two times daily and with each administration a totaldelivered dose of glycopyrrolate of no more than 150 μg and a totaldelivered dose of formoterol of no more than 12 ug are administered tothe patient. In other such embodiments, the methods described herein forachieving clinically significant increases in FEV₁ include administeringa co-suspension as described herein comprising a combination ofglycopyrrolate and formoterol active agents, wherein the co-suspensionis administered to a patient via a metered dose inhaler up to two timesdaily and with each administration a total delivered dose ofglycopyrrolate of no more than 100 μg and a total delivered dose offormoterol of no more than 12 ug are administered to the patient. Inother such embodiments, the methods described herein for achievingclinically significant increases in FEV₁ include administering aco-suspension as described herein comprising a combination ofglycopyrrolate and formoterol active agents, wherein the co-suspensionis administered to a patient via a metered dose inhaler up to two timesdaily and with each administration a total delivered dose ofglycopyrrolate of no more than 80 μg and a total delivered dose offormoterol of no more than 12 ug are administered to the patient. Instill other embodiments, the methods described herein for achievingclinically significant increases in FEV₁ include administering aco-suspension as described herein comprising a combination ofglycopyrrolate and formoterol active agents, wherein the co-suspensionis administered to a patient via a metered dose inhaler up to two timesdaily and with each administration a total delivered dose ofglycopyrrolate of no more than 50 μg and a total delivered dose offormoterol of no more than 12 ug are administered to the patient.

In some embodiments, the methods for achieving clinically significantincreases in IC described herein include administering a co-suspensioncomposition as described herein to a patient via a metered dose inhaler,wherein the co-suspension includes glycopyrrolate and formoterol activeagents, the co-suspension is administered to a patient via a metereddose inhaler up to two times daily, and with each administration totaldelivered doses of no more than 150 μg glycopyrrolate and 12 ugformoterol are administered to the patient. In certain such embodiments,for example, the methods described herein for achieving clinicallysignificant increases in IC include administering a co-suspension asdescribed herein comprising a combination of glycopyrrolate andformoterol active agents, wherein the co-suspension is administered to apatient via a metered dose inhaler up to two times daily and with eachadministration a total delivered dose of glycopyrrolate of no more than100 μg and a total delivered dose of formoterol of no more than 12 ugare administered to the patient. In other such embodiments, the methodsdescribed herein for achieving clinically significant increases in ICinclude administering a co-suspension as described herein comprising acombination of glycopyrrolate and formoterol active agents, wherein theco-suspension is administered to a patient via a metered dose inhaler upto two times daily and with each administration a total delivered doseof glycopyrrolate of no more than 80 μg and a total delivered dose offormoterol of no more than 12 ug are administered to the patient. Instill other embodiments, the methods described herein for achievingclinically significant increases in IC include administering aco-suspension as described herein comprising a combination ofglycopyrrolate and formoterol active agents, wherein the co-suspensionis administered to a patient via a metered dose inhaler up to two timesdaily and with each administration a total delivered dose ofglycopyrrolate of no more than 50 μg and a total delivered dose offormoterol of no more than 12 ug are administered to the patient.

The compositions provided and delivered in the methods described hereinmay include a co-suspension composition including any combination ofactive agents as described herein. For example, in particularembodiments, the methods described herein for achieving a clinicallysignificant increase in FEV₁ or IC include providing a co-suspensioncomposition comprising two or more active agents, wherein at least oneof those active agents is selected from a LABA, LAMA or corticosteroidactive agents as described herein, and administering such composition toa patient experiencing pulmonary inflammation or obstruction via an MDI.In one such embodiment, the active agents included in the co-suspensioncomposition include a combination selected from one of a combination ofLABA and LAMA active agents, a combination of LABA and corticosteroidactive agents, a combination of LAMA and corticosteroid active agents,and a combination of LABA, LAMA and corticosteroid active agents. Inspecific embodiments of the methods described herein, the co-suspensioncomposition provided and administered can be any of the specificco-suspension compositions detailed herein.

The specific examples included herein are for illustrative purposes onlyand are not to be considered as limiting to this disclosure. Moreover,the compositions, systems and methods disclosed herein have beendescribed in relation to certain embodiments thereof, and many detailshave been set forth for purposes of illustration, it will be apparent tothose skilled in the art that the invention is susceptible to additionalembodiments and that certain of the details described herein may bevaried without departing from the basic principles of the invention. Anyactive agents and reagents used in the following examples are eithercommercially available or can be prepared according to standardliterature procedures by those skilled in the art of organic synthesis.The entire contents of all publications, patents, and patentapplications referenced herein are hereby incorporated herein byreference.

Example 1

An exemplary co-suspension composition as described herein was preparedand evaluated. The composition included a combination of glycopyrrolate(GP) and formoterol fumarate (FF) active agents. GP was present in thepropellant as micronized, crystalline active agent particles. It wasco-suspended with spray dried suspending particles that included FFdisposed within the material forming the suspending particle. To achievethis, FF was dissolved in the feedstock used to manufacture thelipid-based suspending particles.

GP active agent particles were formed by micronizing glycopyrrolateusing a jet mill. The particle size distribution of the glycopyrrolateactive agent particles was determined by laser diffraction using a laserdiffraction particle size analyzer, Fraunhofer diffraction mode,equipped with a dry powder dispenser (e.g., Sympatec GmbH,Clausthal-Zellerfeld, Germany). 50% by volume of the active agentparticles exhibited an optical diameter smaller than 1.7 μm, and 90% byvolume exhibited an optical diameter smaller than 3.5 μm.

FF-containing suspending particles were manufactured as follows: 654 mLof a fluorocarbon-in-water emulsion of PFOB (perfluorooctyl bromide)stabilized by a phospholipid was prepared; 26.5 g of the phospholipid,DSPC (1,2-disteroyl-sn-glycero-3-phosphocholine), and 2.4 g of calciumchloride were homogenized in 276 mL of hot water (80° C.) using a highshear mixer; and 142 mL of PFOB were added slowly during homogenization.The resulting coarse emulsion was then further homogenized using a highpressure homogenizer (Model C3, Avestin, Ottawa, CA) at pressures of upto 170 MPa for 5 passes. 552 mg FF was dissolved in 273 ml of warm water(50° C.) and most of the solution was combined with the emulsion using ahigh shear mixer. The emulsion was spray dried in nitrogen using thefollowing spray drying conditions: inlet temperature 95° C.; outlettemperature 68° C.; emulsion feed rate 2.4 ml/min; and total gas flow498 l/min. The final mass fraction of formoterol in the spray driedpowder was 2%.

A second lot of FF-containing suspending particles was manufactured in asimilar fashion. The mass fraction of FF in the spray dried powder was1% for this lot. A third lot of suspending particles was manufacturedwithout FF.

The particle size distribution of the suspending particles (VIVID) wasdetermined by laser diffraction. For both lots of FF containingsuspending particles, 50% by volume were smaller than 3.5 μm and theGeometric Standard Deviation of the distribution was 1.7. For thesuspending particles without FF, 50% by volume were smaller than 3.2 μmand the Geometric Standard Deviation of the distribution was 1.8.

MDIs containing FF, GP or both were prepared by weighing the targetmasses of active agent particles and suspending particles intofluorinated ethylene polymer (FEP) coated aluminum canisters (Presspart,Blackburn, UK) with a 19 mL volume. The canisters were crimp sealed with63 μl valves (# BK 357, Bespak, King's Lynn, UK) and filled with 12.4 gof HFA 134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) byoverpressure through the valve stem. The resulting suspensionconcentrations and the target delivered dose assuming 20% actuatordeposition are given in Table 1a for three different configurations(configurations 1A through 1C). After injecting the propellant, thecanisters were sonicated for 15 seconds and agitated on a wrist actionshaker for 30 minutes. The canisters were fitted with polypropyleneactuators with a 0.3 mm orifice (# BK 636, Bespak, King's Lynn, UK).

TABLE 1a Configurations of the glycopyrrolate-formoterol fumaratecombination co-suspensions of Example 1 Suspending Suspending ParticleSuspending Particle to Ex actuator GP 1 Particle 2 Active dose C_(s) FFC_(s) C_(s) Particle GP FF # [mg/ml] content [mg/ml] [mg/ml] Ratio [μg][μg] 1A 0.48 1.9% 3.2 —  6.7 24 3.2 1B   1% 6.4 — 13.3 1C 1.9% 3.2 3.213.3

The filled MDIs were stored valve down at two different conditions:refrigerated at 5° C. without overwrap and controlled room temperatureat 25° C./60% RH with a foil overwrap. Aerosol performance and delivereddose uniformity tests were carried out at different time points. Aerosolperformance was assessed after manufacturing in accordance with USP<601> (United States Pharmacopoeia Monograph 601). A Next GenerationImpactor (NGI) operated at a flow rate of 30 l/min was used fordetermination of particle size distribution. Sample canisters wereseated into an actuator with two waste actuations and two additionalwaste priming actuations. Five actuations were collected in the NGI witha USP throat attached. The valve, actuator, throat, NGI cups, stages,and filter were rinsed with volumetrically dispensed solvent. The samplesolutions were assayed using a drug-specific chromatographic method. Thefine particle fraction was defined using the sum of stages 3 throughfilter. Delivered dose uniformity through use testing was performedusing a Dose Uniformity Sampling Apparatus as described by USP <601>.Inhalers were seated and primed as described before. Two actuations werecollected and assayed at beginning, middle and end of use.

No trends in aerosol performance or delivered dose uniformity wereobserved for the duration of the study (3 months) or as a function ofstorage temperature. Hence, all aerosol performance test results werepooled. Table 1b lists the average performance of the differentconfiguration. The fine particle dose is the sum of collected mass onstages 3 to filter of the impactor, normalized by the metered dose. Theaverage aerosol performance for all three configurations was equivalent.

TABLE 1b Average aerosol performance for co-suspensions in Example 1MMAD in μm FPD in % # FF GP FF GP 1A 2.8 3.4 52 44 1B 2.9 3.6 51 45 1C2.9 3.6 51 45

Dose content uniformity was tested through canister life for bothactives of the combination product. FIGS. 1 and 2 show the ex-actuatordose for configuration 1A and 1B, respectively, normalized by the actualmetered doses of the canister. Assuming an actuator deposition of 20%the target ex-actuator doses for both actives were 80%. The individualFF and GP doses are represented by dots and triangles, respectively. Theclosed line denotes the mean of the formoterol doses, and the brokenline denotes the mean of the glycopyrrolate doses. FIGS. 3 and 4 showthe ratio of the normalized ex actuator doses for configuration 1A and1B, respectively. The result indicates that the dose ratio remainedconstant through canister life. Furthermore the variability of the doseratio is much lower than that of the individual doses, indicating that aco-suspension with a consistent carrier to active ratio was formed andmaintained through container life.

The results show that, when formulated according to the disclosureprovided herein, combination product co-suspensions are formed withsuspending particles containing one of the active pharmaceuticalingredients, in this case FF. Suspending particle to active agentparticle ratios can be adjusted to achieve targeted dose contentuniformity while maintaining similar aerosol performance.

Example 2

MDIs containing FF, GP or both were prepared at target concentrations of2.4 and 18 μg per actuation for FF and GP respectively. GP active agentwas micronized and had a d₁₀, d₅₀, d₉₀ and span of 0.6, 1.7, 3.6 and 1.9μm respectively as measured by laser diffraction as described Example 1.FF was incorporated into spray dried suspending particles and preparedas described in Example 1, with a composition of 2% FF, 91.5% DSPC and6.5% CaCl₂. The GP, FF and GP+FF MDIs were prepared by weighing thetarget masses of active agent particles and suspending particles intofluorinated ethylene polymer (FEP) coated aluminum canisters (Presspart,Blackburn, UK) with a 19 mL volume. The canisters were crimp sealed with50 μl valves (# BK 357, Bespak, King's Lynn, UK) and filled with 10.2 gof HFA 134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) byoverpressure through the valve stem. After injecting the propellant, thecanisters were sonicated for 15 seconds and agitated on a wrist actionshaker for 30 minutes. The canisters were fitted with polypropyleneactuators with a 0.3 mm orifice (# BK 636, Bespak, King's Lynn, UK).

Long term aerosol stability and delivery characteristics of the MDIcompositions were assessed. In particular the aerosol particle sizedistribution and delivered dose characteristics of such compositionswere evaluated as in accordance with USP <601> as described in Example1, under various conditions and, in some instances, for periods of timeextending up to 12 months. For example, as is shown in FIG. 5, thedelivered dose uniformity provided by the compositions preparedaccording to Example 1 was substantially preserved, even after 12 monthsstorage of such compositions at 5° C. or after 4.5 months at 25° C. and60% relative humidity (RH) for samples stored inside aluminum foilpouches to minimize water ingress into the MDI canister (i.e.,“protected storage”).

The aerosol performance of such compositions was also evaluatedthroughout unprotected storage conditions extending up to 12 months andprotected storage conditions extending up to 6 months. As is shown inFIG. 6, the GP and FF particle size distributions provided by thisco-suspension composition were substantially preserved after 12 monthsof protected storage at 5° C. and six months of unprotected storageconditions at 25° C. and 60% RH. As is shown in FIG. 7, even understressed conditions (40° C., 75% RH), the compositions showed nonoticeable degradation in the particle size distribution of GP and FFdelivered from the metered dose inhalers after six months.

In order to evaluate whether the combination of GP and FF within asingle formulation would result in the degradation of the aerosolproperties relative to compositions including a single active agent, theaerosol properties of co-suspension compositions were assessed relativeto suspension compositions including only a single active agent.

As can be seen in FIG. 8, the aerosol performance of the combinationco-suspension composition including both GP and FF active agent was nodifferent than the aerosol performance achieved by suspensioncompositions including either GP or FF alone demonstrating that theaerosol properties of the individual active agents are substantially thesame when achieved from the single component or dual combinationco-suspensions.

Example 3

The pharmacokinetics and safety of a combination co-suspension metereddose inhaler containing glycopyrrolate and formoterol fumarate wereevaluated in a clinical trial. The clinical trial was a single-center,randomized, double-blind, single dose, four-period, four-treatmentcrossover study used to evaluate four inhaled treatments administered byMDI. The four treatments included a Formoterol Fumarate (FF) InhalationAerosol, a Glycopyrrolate (GP) Inhalation Aerosol, a GP+FF InhalationAerosol, and consecutive delivery of the GP Inhalation Aerosol followedimmediately by delivery of the FF Inhalation Aerosol. The GP+FFInhalation Aerosol as well as the FF Inhalation Aerosol and GPInhalation Aerosol were prepared as described in Example 2. The GP+FFInhalation Aerosol was also labeled the “fixed” combination of GP andFF, while the treatment calling for consecutive delivery of the GPInhalation Aerosol followed immediately by delivery of the FF InhalationAerosol was labeled the “loose” combination of GP and FF.

Subjects were randomized in to the study and assigned one of fourtreatment sequences, with each treatment sequence including all fourstudy treatments. Each subject received four single dose treatmentsseparated by 7 to 21 days. Sixteen subjects were enrolled and analyzedfor safety. Three subjects were excluded from the PK analysis as aresult of not receiving one or more of the four treatments, and anadditional two subjects were excluded from the PK analysis asnon-evaluable due to dosing errors arising from poor inhalationtechnique.

The GP+FF Inhalation Aerosol was administered to provide each subject a72 μg dose of GP and a 9.6 μg dose of FF (four actuations, 18 μg GP and2.4 μg FF per actuation). The GP Inhalation Aerosol was administered toprovide each subject a 72 μg dose of GP (four actuations, 18 μg GP peractuation). The FF Inhalation Aerosol was administered to provide eachsubject a 9.6 μg dose of FF (four actuations, 2.4 μg FF per actuation).For blinding purposes each of the preceding three treatments werepreceded by four actuations of placebo MDI. The loose combination of GPInhalation Aerosol followed by FF Inhalation Aerosol was administered toprovide each subject a 72 μg dose of GP and a 9.6 μg dose of FF (fouractuations, 18 μg GP per actuation followed by four additionalactuations, 2.4 μg FF per actuation).

Both the loose and fixed combinations of GP and FF were safe andwell-tolerated, with the fixed combination providing a safety profilesimilar to that observed for the other three treatments evaluated in thetrial. Blood samples were collected pre-dose and at 2, 5, 15, and 30minutes, as well as 1, 2, 4, 6, 8, and 12 hours post-dose fordetermining the plasma concentrations of GP and FF that were used tocalculate various PK parameters. Plasma concentration time profiles forboth GP and FF in the 12 hour period immediately following dosing areprovided in FIG. 9. As can be seen in FIG. 9, administration of GP andFF from the fixed combination resulted in plasma concentrations of GPand FF following administration comparable to those resulting fromadministration of the loose combination of GP and FF. As was noted forthe in-vitro delivered dose and particle size distribution performancedescribed in Example 2, no combination effect was observed in-vivo forthe fixed combination GP+FF Inhalation Aerosol.

Example 4

An exemplary dual co-suspension composition according to the presentdescription was produced and metered dose inhalers incorporating thecomposition were prepared. The composition included a combination ofglycopyrrolate (GP) and formoterol fumarate (FF), with each beingprovided as a micronized, crystalline material. A combinationcrystalline co-suspension MDI was manufactured by semi-automatedsuspension filling. The dual co-suspension consisted of a combination oftwo microcrystalline active pharmaceutical ingredients (also referred toas “APIs” or “API” in the singular), GP and FF, co-suspended withsuspending particles in HFA 134a propellant. The dual co-suspension wasformulated to provide a delivered dose of 18 μg GP per actuation and 4.8μg FF per actuation. In preparing the dual co-suspension compositions,in certain compositions, the FF API material used was denoted as“coarse”, while in other compositions, the FF API material used wasdenoted as “fine.” Whether the co-suspension compositions incorporatedcourse or fine FF, the compositions were formulated to provide adelivered FF dose of 4.8 μg per actuation. The particle sizecharacteristics for the course FF, fine FF and GP API materials used informulation the co-suspension compositions described in this Example aredetailed in Table 2. In addition to the dual co-suspension compositions,a monotherapy co-suspension composition incorporating only FF activeagent material was formulated. The FF monotherapy co-suspension utilizedcoarse FF API. A monotherapy MDI was manufactured using such FFmonotherapy co-suspension, and the FF monotherapy MDI was formulated andmanufactured provide a delivered dose of 4.8 μg FF per actuation.

Suspending particles were manufactured via spray dried emulsion at afeed stock concentration of 80 mg/mL with a composition of 93.44% DSPC(1,2-Distearoyl-sn-Glycero-3-Phosphocholine) and 6.56% anhydrous calciumchloride (equivalent to a 2:1 DSPC:CaCl₂ mole/mole ratio). During theemulsion prep, DSPC and CaCl₂ was dispersed with a high shear mixer at8000-10000 rpm in a vessel containing heated water (80±3° C.) with PFOBslowly added during the process. The emulsion was then processed with 6passes in a high pressure homogenizer (10000-25000 psi). The emulsionwas then spray dried via a spray dryer fitted with a 0.42″ atomizernozzle with a set atomizer gas flow of 18 SCFM. The drying gas flow ratewas set to 72 SCFM with an inlet temperature of 135° C., outlettemperature 70° C., and an emulsion flow rate of 58 mL/min.

For the MDI manufacturing, a drug addition vessel (DAV) was prepared forsuspension filling in the following manner: first adding half ofsuspending particle quantity, next filling microcrystalline materials,and lastly adding the remaining half of suspending particles to the top.Materials were added to the vessel in a humidity controlled environmentof <10% RH. The DAV was then connected to a 4 L suspension vessel andflushed with HFA 134a propellant and then mixed with gently to form aslurry. The slurry is then transferred back to the suspension mixingvessel and diluted with additional HFA-134a to form the final suspensionat target concentration stirring gently with an impeller. Thetemperature inside the vessel was maintained at 21-23° C. throughout theentire batch production. After recirculation for 30 min the suspensionwas filled into 14 mL fluorinated ethylene polymer (FEP) coated aluminumcanisters (Presspart, Blackburn, UK) through 50 μl valves (Bespak,King's Lynn, UK). Sample canisters were the selected at random for totalcanister analysis to ensure correct formulation quantities. The opticaldiameter and particle size distribution of two lots of micronizedformoterol particles was determined by laser diffraction as described inExample 1. Table 2 lists the d₁₀, d₅₀ and d₉₀ values for the differentlots of micronized material used. d₁₀, d₅₀ and d₉₀ denote the particlesize at which the cumulative volume distribution reported by theparticle sizing instrument reaches 10%, 50% and 90%, respectively.

The particle size distributions provided by both dual co-suspensionformulations prepared in accordance with this Example 4 were compared tothe particle size distribution provided by a co-suspension compositionsprepared according to Example 1. The results of this comparison areprovided in Table 3, where “% FPF FF” and “% FPF GP” represent the fineparticle mass of the specified active agent on Stages 3 through filterof an NGI, divided by actuator mass, and multiplied by 100.

TABLE 2 Particle Size Distributions for micronized Formoterol Fumarateand Glycopyrrolate used to prepare Dual Co-Suspensions Designation d₁₀(μm) d₅₀ (μm) d₉₀ (μm) Span Coarse FF API 0.6 1.9 4.4 2.0 Fine FF API0.5 1.3 2.3 1.5 GP API 0.5 1.3 3.0 1.9

TABLE 3 Particle Size Distributions for Different, Exemplary GP/FFCo-suspensions MMAD % FPF MMAD % FPF MMAD % FPF FF FF GP GP DSPC DSPCDual Co- 3.4 59% 2.9 65% 2.9 64% Suspension 1 (FF coarse) Dual Co- 2.762% 3.0 62% 3.1 62% Suspension 2 (FF fine) Spray-dried 2.7 66% 2.9 65%not not FF tested tested

The aerosol performance of the dual co-suspension compositions preparedaccording to this Example was evaluated and compared to theco-suspension composition prepared according to Example 1, with aerosolperformance being assessed as described in Example 1. The results ofsuch comparisons are provided in FIG. 10 through FIG. 12. As is easilyappreciated by reference to these figures, regardless of whether thecrystalline formoterol material used in providing the dual co-suspensionwas fine or coarse, the FF and GP particle size distributions for thedual co-suspension compositions were substantially the same as thoseachieved by the co-suspension composition prepared according to Example1.

In addition, the delivered dose uniformity for GP and FF provided by thedual co-suspension compositions as described in this Example wasassessed in as described in Example 1. The results of this assessmentare illustrated in FIG. 13. The dual co-suspension formulations provideddesirable DDU characteristics for both GP and FF as all actuationsdelivered the expected dose within ±25% of the mean.

Example 5

The formulation of a dual co-suspension composition of salmeterolxinafoate (SX) active agent particles and fluticasone propionate (FP)active agent particles is described. Both FP and SX are present in thepropellant as a micronized, crystalline particles. The two species ofmicronized active agent particles are co-suspended with spray driedsuspending particles.

Micronized SX (4-hydroxy-α1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate) wasreceived by the manufacturer (Inke SA, Germany) and used as active agentparticles. The particle size distribution of the SX was determined bylaser diffraction. 50% by volume of the micronized particles exhibitedan optical diameter smaller than 2 μm, and 90% by volume exhibited anoptical diameter smaller than 3.9 μm.

Micronized FP(S-(fluoromethyl)6^(α),9-difluoro-11^(β)-17-dihydroxy-16^(α)-methyl-3-oxoandrosta-1,4-diene-17-carbothioate,17-propionate) was received as micronized by the manufacturer (HovioneFarmaCiencia SA, Loures Portugal) and used as active agent particles.The particle size distribution of the FP was determined by laserdiffraction. 50% by volume of the micronized particles exhibited anoptical diameter smaller than 2.6 μm, and 90% by volume exhibited anoptical diameter smaller than 6.6 μm.

Suspending particles were manufactured as follows: 150 mL of afluorocarbon-in-water emulsion of PFOB (perfluorooctyl bromide)stabilized by a phospholipid was prepared; 12.3 g of the phospholipid,DSPC (1,2-disteroyl-sn-glycero-3-phosphocholine) and 1.2 g of calciumchloride were homogenized in 100 mL of hot water (70° C.) using a highshear mixer; and 65 mL of PFOB were added slowly during homogenization.The resulting coarse emulsion was then further homogenized using a highpressure homogenizer (Model C3, Avestin, Ottawa, CA) at pressures of upto 140 MPa for 3 passes.

The emulsion was spray dried in nitrogen using the following spraydrying conditions: Inlet temperature 90° C.; outlet temperature 69° C.;emulsion feed rate 2.4 ml/min; and total gas flow 498 l/min. Theparticle size distribution of the suspending particles, VIVID, wasdetermined by laser diffraction. 50% by volume of the suspendingparticles were smaller than 2.7 μm, the Geometric Standard Deviation ofthe distribution was 2.0. Additionally, the aerodynamic particle sizedistribution of the suspending particles was determined with atime-of-flight particle sizer. 50% by volume of the suspending particleshad an aerodynamic particle diameter smaller than 1.6 μm. The largedifference between aerodynamic particle diameter and optical particlediameter indicates that the suspending particles had a low particledensity <0.5 kg/l. This was verified by electron microscopy, whichconfirmed that the suspending particles exhibited a hollow, thin-walledmorphology.

MDIs were prepared by weighing the target masses of micronized FP, SX,and suspending particles into fluorinated ethylene polymer (FEP) coatedaluminum canisters (Presspart, Blackburn, UK) with a 19 mL volume. Thecanisters were crimp sealed with 63 μl valves (# BK 357, Bespak, King'sLynn, UK) and filled with 10 ml of HFA 134a (1,1,1,2-tetrafluoroethane)(Ineos Fluor, Lyndhurst, UK) by overpressure through the valve stem.After injecting the propellant, the canisters were sonicated for 15seconds and agitated on a wrist action shaker for 30 minutes. Thecanisters were fitted with polypropylene actuators with a 0.3 mm orifice(# BK 636, Bespak, King's Lynn, UK). Aerosol performance was assessedshortly after manufacturing in accordance with USP 601, as described inExample 1. Results are reported below in Table 4.

TABLE 4 Results for a co-suspension of Fluticasone Propionate (FP) andSalmeterol Xinafoate (SX) of Example 5 Sus- Target Target pending De-De- particle livered livered FP SX FP SX FP SX conc. Dose FP Dose SX DDUDDU FPF FPF MMAD MMAD 5.9 12 μg 25 μg 6.1% 6.1% 27% 49% 4.1 μm 3.4 μmmg/mL RSD* RSD* *no trend observed

The delivered dose uniformity through use was tested and all individualdelivered doses were within ±20% of mean, at 6.1% relative standarddeviation (also referred to as “RSD”). Visual observation of theco-suspension was conducted in glass vials and no sedimentation ofactive agent particles was observed. The vials were left to settle for24 hours without agitation. The suspension flocculated slowly and formeda homogeneous, single cream layer.

Example 6

The formulation of a combination co-suspension composition of salmeterolxinafoate (SX) active agent particles and fluticasone propionate (FP)suspending particles is described. SX is present in the propellant as amicronized, crystalline particle. It is co-suspended with spray driedsuspending particles that have micronized FP disposed into the materialforming the suspending particles. To achieve this, FP crystals aresuspended in the feedstock used to manufacture the lipid-basedsuspending particles. The FP and SX used to form the active agentparticles and suspending particles referenced in this example were asdescribed in Example 5.

FP-containing suspending particles were manufactured as follows: 200 mLof a fluorocarbon-in-water emulsion of PFOB stabilized by a phospholipidwas prepared; 3.3 g of the phospholipid (DSPC) and 0.8 g of micronizedFP were dispersed and 0.3 g of calcium chloride dihydrate was dissolvedin 100 mL of warm water (70° C.) using a high shear mixer; and 44 mL ofPFOB was added slowly during dispersion. The resulting coarse emulsionwas then further homogenized using a high pressure homogenizer at 140MPa for 3 passes. The homogenization reduced the particle size of thesuspended FP crystals. The emulsion was spray dried in nitrogen usingthe following spray drying conditions: inlet temperature 95° C.; outlettemperature 72° C.; emulsion feed rate 2.4 ml/min; and total gas flow525 l/min.

MDIs were prepared by weighing the target masses of micronized SX activeagent particles and FP-containing suspending particles into fluorinatedethylene polymer (FEP) coated aluminum canisters (Presspart, Blackburn,UK) with a 19 mL volume. The canisters were crimp sealed with 63 μlvalves (# BK 357, Bespak, King's Lynn, UK) and filled with 10 ml of HFA134a (1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) byoverpressure through the valve stem. After injecting the propellant, thecanisters were sonicated for 15 seconds and agitated on a wrist actionshaker for 30 minutes. The canisters were fitted with polypropyleneactuators with a 0.3 mm orifice (# BK 636, Bespak, King's Lynn, UK).Aerosol performance was assessed shortly after manufacturing inaccordance with USP 601 as previously described in Example 1. Resultsare reported below in Table 5.

TABLE 5 Results for a Co-suspension of Salmeterol Xinafoate (SX) ActiveAgent Particles with Fluticasone Propionate-containing SuspendingParticles. FP- Target Target Sus- De- De- pending livered livered FP SXFP SX FP SX conc. Dose FP Dose SX DDU DDU FPF FPF MMAD MMAD 4.2 60 μg 13μg 9.0% 13% 55% 51% 2.8 μm 3.0 μm mg/mL RSD* RSD* *with a slight upwardtrend

The delivered dose uniformity through use was tested and all individualdelivered doses were within ±25% of mean, at 9.0% RSD for FP and 13% RSDfor SX. Visual observation of the co-suspension was conducted in glassvials and no sedimentation of active agent particles was observed. Thevials were left to settle for 24 hours without agitation. The suspensionflocculated slowly and formed a homogeneous, single cream layer, showingno indication of separation of SX and suspending particles.

Example 7

The formulation of a dual co-suspension composition including budesonideactive agent particles and mometasone furoate active agent particles isdescribed. Budesonide (BD) and mometasone furoate (MF) were present inthe propellant as a micronized, crystalline particles and areco-suspended with spray dried suspending particles.

BD, 16,17-(butylidenebis(oxy))-11,21-dihydroxy-,(11-β,16-α)-pregna-1,4-diene-3,20-dione, was received micronized by themanufacturer (AARTI, Mumbai, India) and used as active agent particles.The particle size distribution of the BD was determined by laserdiffraction. 50% by volume of the micronized particles exhibited anoptical diameter smaller than 1.9 μm, and 90% by volume exhibited anoptical diameter smaller than 4.3 μm.

MF,9α,21-dichloro-11β,17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione17-(2-furoate), was received micronized by the manufacturer (AARTI,Mumbai, India) and used as active agent particles. The particle sizedistribution of the MF was determined by laser diffraction. 50% byvolume of the micronized particles exhibited an optical diameter smallerthan 1.6 μm, and 90% by volume exhibited an optical diameter smallerthan 3.5 μm.

Suspending particles were manufactured as follows: 500 mL of afluorocarbon-in-water emulsion of PFOB (perfluorooctyl bromide)stabilized by a phospholipid was prepared; 18.7 g of the phospholipid,DSPC (1,2-disteroyl-sn-glycero-3-phosphocholine) and 1.3 g of calciumchloride were homogenized in 400 mL of hot water (75° C.) using a highshear mixer; and 100 mL of PFOB were added slowly during homogenization.The resulting coarse emulsion was then further homogenized using a highpressure homogenizer (Model C3, Avestin, Ottawa, CA) at pressures of upto 170 MPa for 5 passes. The emulsion was spray dried in nitrogen usingthe following spray drying conditions: inlet temperature 95° C.; outlettemperature 72° C.; emulsion feed rate 2.4 ml/min; and total gas flow498 l/min.

MDIs were prepared by weighing the target masses of micronized activeand suspending particles into coated glass vials with a 15 mL volume.The canisters were crimp sealed with 63 μl valves (Valois, LesVaudreuil, France) and filled with 9.2 g of HFA 134a(1,1,1,2-tetrafluoroethane) (Ineos Fluor, Lyndhurst, UK) by overpressurethrough the valve stem. After injecting the propellant, the canisterswere sonicated for 15 seconds and agitated on a wrist action shaker for30 minutes. The suspension concentrations were 0.8 mg/ml for BD activeagent particles, 1.1 mg/ml for MF active agent particles, and 6 mg/mlfor the suspending particles. The suspending particle to active agentparticle ratio was 7.5 for BD and 5.5 for MF. Target ex actuator doseswere 40 μg for BD and 55 μg for MF.

Visual observation of the co-suspended configurations showed nosedimentation of active agent particles. The vials were left to settlefor 16 hours without agitation. No active agent particles were visibleat the bottom of the co-suspension vials. The results showed thatcrystalline budesonide and mometasone furoate material forming thedifferent species of active agent particles associated with thesuspending particles, formed a co-suspension in the configurationsdisclosed herein. The association between active agent particles andsuspending particles was strong enough to overcome buoyancy forces assettling of the active agent particles was successfully inhibited.

Example 8

Dual co-suspension compositions were prepared with suspending particlesincluding either mometasone furoate (MF) or budesonide (BD), and MDIsincorporating the composition were prepared. The co-suspensioncomposition included a combination of crystalline glycopyrrolate (GP)and formoterol fumarate (FF) active agent particles co-suspended withsuspending particles including either MF or BD. Each of the APIs wereprovided as a micronized, crystalline material.

Suspending particles containing 50% (w/w) of either BD or MF weremanufactured as follows: high shear homogenization of a dispersioncontaining 2.8 g of DSPC (1,2-Distearoyl-sn-Glycero-3-Phosphocholine),and 0.26 g of calcium chloride in 400 mL of hot water (75° C.) using ahigh shear mixer was performed while 56.6 g of PFOB were added slowly.Micronized MF or BD (in 1:1 weight proportion to DSPC) was added to theresulting coarse emulsion, which was further homogenized using a highpressure homogenizer (Model C3, Avestin, Ottawa, CA) at pressures of upto 170 MPa for 3 to 5 passes. The emulsion was spray dried using thefollowing spray drying conditions: inlet temperature 90-95° C.; outlettemperature 95-72° C.; emulsion feed rate 2-8 mL/min; total dry nitrogenflow 525-850 L/min. The particle size distribution of the resultingpowders was determined by laser diffraction, 50% by volume of thesuspending particles were smaller than 1.8 μm, the span of thedistribution was 1.6 μm.

Canisters containing either 50% (w/w) MF or BD containing suspendingparticles were filled with HFA 134a propellant, targeting a 50 or 100μg/actuation of MF or BD, respectively. Their aerosol particle sizedistributions were determined according to the methods described inExample 1, and results are shown in Table 6. A comparable series ofcanisters containing MF or BD containing suspending particles incombination with GP and FF active agent particles were produced.Sufficient micronized GP and FF API material was added to such canistersin amounts sufficient to provide targeted delivered doses of 36μg/actuation and 6 μg/actuation for GP and FF, respectively. Additionalplacebo suspending particles prepared as described herein but free ofany active agent (also referred to as “placebo” suspending particles)were added to certain to reach a total co-suspension concentration of5.5 mg/ml.

The aerosol particle size distributions provided by the co-suspensioncompositions prepared according to this Example were determined asdescribed in Example 1, with the results are shown in Table 7. The massmean aerodynamic diameter of the corticosteroid in the single componentsuspensions is equivalent to the one obtained in the triple combinationformulations prepared with two different species of active agentparticles co-suspended with BD or MF containing suspending particles. Aswas true of the co-suspension compositions containing a combination oftwo different active agents, the triple co-suspension compositionsprepared according to the present description avoided a combinationeffect.

TABLE 6 Suspension MDIs in HFA 134a propellant containing corticosteroidsuspending particles. Aerosol properties, mass aerodynamic diameter andfine particle fraction determined by drug specific cascade impaction.Suspension. Concentration MMAD FPF (mg/ml) (μm) (%) Mometasone 5.5 2.8861.0 Furoate Budesonide 5.6 3.20 61.7

TABLE 7 Triple combination suspension MDIs in HFA 134a propellantincluding corticosteroid containing suspending particles (MometasoneFuroate or Budesonide), a LAMA (Glycopyrrolate) and a LABA (FormoterolFumarate). Aerosol properties, mass mean aerodynamic diameter and fineparticle fraction determined by drug specific cascade impaction.Suspension Concentration MMAD FPF (mg/ml) Drug (μm) (%) Triple A 2.3Formoterol 3.96 44.4 Glycopyrrolate 3.71 49.0 Mometasone 2.90 61.6Triple B* 5.6 Formoterol 3.52 44.4 Glycopyrrolate 3.34 49.0 Mometasone2.54 61.6 Triple C 5.5 Formoterol 3.89 47.1 Glycopyrrolate 3.74 50.0Budesonide 3.12 63.1 *with added placebo suspending particles

Example 9

A triple co-suspension composition according to the present descriptionwas produced and MDIs incorporating the composition were prepared. Thecomposition included a combination of glycopyrrolate (GP), formoterolfumarate (FF), and mometasone furoate (MF) active agent particles, witheach being provided as a micronized, crystalline API material.

A triple co-suspension MDI was manufactured by semi-automated suspensionfilling. The triple co-suspension consisted of a combination of threemicrocrystalline active pharmaceutical ingredients forming threedifferent species of active agent particles: MF (corticosteroid); GP(LAMA); and FF (LABA). These three different species of active agentparticles were co-suspended with suspending particles in HFA 134apropellant. The triple co-suspension was formulated to the followingdelivered dose targets: 50 μg per actuation MF; 36 per actuation GP; and4.8 μg per actuation FF. In addition to the triple co-suspension, amonotherapy co-suspension including only MF was produced. Themonotherapy MF co-suspension included MF active agent particlesco-suspended in the propellant with suspending particles as described inthis Example, and was formulated to provide a target delivered dose of50 μg per actuation MF.

Suspending particles were manufactured via spray dried emulsion at afeed stock concentration of 80 mg/mL with a composition of 93.44% DSPC(1,2-Distearoyl-sn-Glycero-3-Phosphocholine) and 6.56% anhydrous calciumchloride (equivalent to a 2:1 DSPC:CaCl₂ mole/mole ratio). During theemulsion prep, DSPC and CaCl₂ were dispersed with a high shear mixer at8000-10000 rpm in a vessel containing heated water (80±3° C.) with PFOBslowly added during the process. The emulsion was then processed with 5passes in a high pressure homogenizer (10000-25000 psi). The emulsionwas then spray dried via a spray dryer fitted with a 0.42″ atomizernozzle with a set atomizer gas flow of 18 SCFM. The drying gas flow ratewas set to 72 SCFM with an inlet temperature of 135° C., outlettemperature 70° C., and an emulsion flow rate of 58 mL/min.

For MDI manufacturing, a drug addition vessel (DAV) was prepared forsuspension filling in the following manner: first adding half ofsuspending particle quantity, next filling microcrystalline materials,and lastly adding the remaining half of suspending particles to the top.Materials were added to the vessel in a humidity controlled environmentof <10% RH. The DAV was then connected to a 4 L suspension vessel andflushed with HFA 134a propellant and then mixed with a magnetic stirbar. The temperature inside the vessel was maintained at 21-23° C.throughout the entire batch production. After recirculation of the batchfor 30 min canisters were filled with the suspension mixture through 50μL EPDM valves. Sample canisters were the selected at random for TotalCanister Analysis to ensure correct formulation quantities. The freshlymanufactured triple co-suspension MDI batch was then placed on one weekquarantine before initial product performance analysis. The mometasonefuroate only MDI was manufactured by suspension filling in the samemanner.

The primary particle size distribution of all microcrystalline APIs wasdetermined by laser diffraction as described in Example 1, results areshown in Table 9. Aerodynamic particle size distribution and mass meanaerodynamic diameter of all components upon actuation of the suspensionMDIs was determined by drug specific cascade impaction as described inExample 1 and are shown in Table 9.

TABLE 9 Triple microcrystalline Co-Suspension in HFA 134a propellantMDI. Primary particle size distribution determined by laser diffraction(Sympatec). Materials x10 (μm) x50 (μm) x90 (μm) Span MicronizedMometasone 0.4 1.1 2.8 2.2 Furoate (MF) Micronized Glycopyrrolate 0.51.3 3.0 1.8 (GP) Micronized Formoterol 0.6 1.9 4.1 1.8 FumarateDihydrate (FF)

TABLE 10 Triple co-suspension MDIs in HFA 134a propellant containingmicrocrystalline Corticosteroid (Mometasone Furoate), LABA (FormoterolFumarate) and a LAMA (Glycopyrrolate). Aerosol properties, mass meanaerodynamic diameter and fine particle fraction were determined by drugspecific cascade impaction (NGI). Suspension Concentration MMAD FPF(mg/ml) Drug (μm) (%) Triple 6 Mometasone 3.18 62.6 (Corticosteroid,Formoterol 3.50 59.5 LABA, LAMA) Glycopyrrolate 2.97 64.1 Mono 6Mometasone 3.36 58.9 (Corticosteroid)

Aerosol performance and delivered dose uniformity achieved by the tripleco-suspensions prepared according to this Example were evaluatedaccording to the description provided in Example 1. FIG. 14 illustratesthe GP, FF and MF DDU achieved from two canisters containing MF only andtwo canisters containing NIF, GP and FF prepared according to thisExample. The DDU of MF delivered from the MF monotherapy configurationis equivalent to the one achieved with the triple co-suspensioncomposition. The aerosol performance of the triple co-suspensioncomposition prepared according to this example was also assessedrelative to formulations containing a combination of only two activeagents, FF and GP. The aerodynamic particle size distribution of FF andGP are equivalent whether delivered from the compositions containing twoactive agents or three active agents as shown in FIGS. 15 and 16,respectively.

As was true of the co-suspension compositions containing a combinationof two different active agents, the triple co-suspension compositionsprepared according to the present description avoided a combinationeffect.

Example 10

Exemplary triple co-suspension compositions according to the presentdescription were produced and metered dose inhalers incorporated in thecomposition were prepared. The triple co-suspensions includedglycopyrrolate (GP) or tiotropium bromide (TB) in combination withformoterol fumarate (FF), and mometasone furoate (MF) active agents,with each API being used as micronized, crystalline material.

Two separate suspension MDI batches containing three activepharmaceutical ingredients (APIs), a corticosteroid, a LAMA and a LABAwere prepared. The APIs were provided as microcrystalline materials thatserved as the active agent particles co-suspended with suspendingparticles prepared as described herein. The triple co-suspensioncompositions prepared as described in this Example were prepared byadding the active agent particles and suspending particles to an HFA134a propellant.

The first triple co-suspension batch (Triple GFM) was formulated to thefollowing delivered dose targets: 40 μg per actuation MF; 13 μg peractuation GP; and 4.8 μg per actuation FF. The active agent particleswere co-suspended with suspending particles manufactured using anemulsion composed of 93.46% DSPC(1,2-Distearoyl-sn-Glycero-3-Phosphocholine) and 6.54% anhydrous calciumchloride spray dried with an 80 mg/mL feed concentration. The DSPC:CaCl₂molar ratio of the suspending particles was 2:1. The suspendingparticles were combined with the active agent particles in propellantfor a formulation target of 6 mg/ml suspending particle concentration.The primary particle sizes of the microcrystalline active agentparticles, determined by Sympatec laser diffraction measurements asdescribed in Example 1, are displayed below in Table 11.

The second triple co-suspension batch (TFM) was prepared using adifferent LAMA API, anhydrous tiotropium bromide (TB) to replace GP. Thesecond triple co-suspension was formulated to the following delivereddose targets: 50 μg per actuation MF; 9 μg per actuation TB; and 4.8 μgper actuation FF. The suspending particles were prepared as described inrelation to the Triple GFM co-suspension, and the active agent particleswere co-suspended with the suspending particles at a targeted suspensionconcentration of 6 mg/ml. The primary particle sizes of themicrocrystalline active agent particles, determined by Sympatec laserdiffraction measurements as described in Example 1, are displayed belowin Table 12.

MDIs were prepared using the Triple GFM and Triple TFM co-suspensioncompositions, and the aerosol properties, fine particle fraction, andmass median aerodynamic diameter were determined as described inExample 1. Table 13 sets out the MMAD and FPF performance for Triple GFMand Triple TFM, while the desirable aerosol properties achieved by theTriple GFM and Triple TFM co-suspensions are shown in FIG. 17 (showingthe aerodynamic particle size distribution of GP and TB obtained fromTriple GFM and Triple TFM, respectively).

TABLE 11 Triple GFM primary particle size distribution determined bylaser diffraction (Sympatec). Materials d₁₀ (μm) d₅₀ (μm) d₉₀ (μm) SpanMicronized Mometasone 0.4 1.0 2.3 1.9 Furoate Micronized Glycopyrrolate0.5 1.4 3.4 2.1 Micronized Formoterol 0.5 1.4 2.7 1.9 Fumarate Dihydrate

TABLE 12 Triple TFM primary particle size distribution determined bylaser diffraction (Sympatec). Materials d₁₀ (μm) d₅₀ (μm) d₉₀ (μm) SpanMicronized Mometasone 0.4 1.1 2.8 2.2 Furoate Micronized Tiotropium 0.51.3 3.9 2.7 Bromide Anhydrous Micronized Formoterol 0.6 1.9 4.1 1.9Fumarate Dihydrate

TABLE 13 Triple GFM and Triple TFM aerosol properties, mass meanaerodynamic diameter and fine particle fraction determined by drugspecific cascade impaction Suspension Concentration MMAD FPF (mg/ml)Drug (μm) (%) Triple GFM 6 Formoterol 2.80 65.3 Glycopyrrolate 2.90 49.5Mometasone 3.10 49.2 Triple TFM 6 Formoterol 3.82 42.4 Tiotropium 3.7942.0 Mometasone 4.00 43.6

Example 11

Exemplary dual co-suspension compositions according to the presentdescription were produced and MDIs incorporating the dual co-suspensioncompositions were prepared. The compositions included a combination ofglycopyrrolate (GP) and formoterol fumarate (FF), with each beingprovided as a micronized, crystalline material with particle sizedistribution as shown in Table 14. The microcrystalline GP and FFmaterials provided two species of active agent particles, whilesuspending particles were prepared as described in Example 4. Inpreparing the dual co-suspensions described in this Example, the GPactive agent particles, FF active agent particles, and suspendingparticles were combined in an HFA 134a propellant.

The dual co-suspensions described in this example were prepared by firstdispensing the appropriate quantities of GP and FF active agentparticles and suspending particles into a drug addition vessel (DAV)inside a humidity controlled chamber (RH<5%). The DAV is then sealedunder a nitrogen atmosphere and connected to the suspension vesselcontaining 12 kg of HFA-134a. A slurry was then formed by adding 0.5-1kg of HFA-134a into the DAV, which is then removed from the suspensionvessel and gently swirled. The slurry is then transferred back to thesuspension mixing vessel and diluted with additional HFA-134a to formthe final suspension at target concentration stirring gently with animpeller. The suspension is then recirculated via a pump to the fillingsystem for a minimum time prior to initiation of filling. Mixing andrecirculation continue throughout the filling process. Valves are placedonto MDI canisters and then purged of air either by a vacuum crimpingprocess, or an HFA-134a purging process, followed by valve crimping. Thecrimped canisters are then filled through-the-valve with the appropriatequantity of suspension, adjusted by the metering cylinder.

TABLE 14 Glycopyrrolate and Formoterol Fumarate particle sizedistributions. Designation d₁₀ (μm) d₅₀ (μm) d₉₀ (μm) Span FF API 0.61.9 4.1 1.8 GP API 0.5 1.3 3.0 1.9

The suspension for pressure filling is prepared by first dispensing theappropriate quantities of micronized glycopyrrolate and formoterolfumarate crystals and suspending particles to a drug addition vessel(DAV), inside a humidity controlled chamber (RH<5%). In the currentexample the suspending particle carrier was added in three equalportions intercalating the addition of GP and FF after the first andsecond addition respectively. The DAV is then sealed under a nitrogenatmosphere and connected to the suspension vessel containing 12 kg ofHFA-134a. A slurry was then formed by adding 0.5-1 kg of HFA-134a intothe DAV, which is then removed from the suspension vessel and gentlyswirled. The slurry is then transferred back to the suspension mixingvessel and diluted with additional HFA-134a to form the final suspensionat target concentration stirring gently with an impeller. The suspensionis then recirculated via a pump to the filling system for a minimum timeprior to initiation of filling. Mixing and recirculation continuethroughout the filling process. Valves are placed onto canisters andthen purged of air either by a vacuum crimping process, or an HFA-134apurging process followed by valve crimping. The crimped canisters arethen filled through-the-valve with the appropriate quantity ofsuspension, adjusted by the metering cylinder.

MDIs containing the dual co-suspensions described in this Example wereprepared to contain two different doses GP and FF. Specifically, a firstrun of dual co-suspension compositions were prepared to provide 18 μgper actuation GP and 4.8 μg per actuation FF (“low dose”), and a secondrun of dual co-suspension compositions were prepared to provide 36 peractuation GP and 4.8 μg per actuation FF (“high dose”). In addition tothe dual co-suspensions compositions, monotherapy FF and GPco-suspension compositions were prepared. The monotherapy co-suspensioncompositions were prepared as described for the dual co-suspensions,except that they included only one species of active agent particles(either GP or FF). The monotherapy co-suspensions were formulated andmonotherapy MDIs prepared to provide the following targeted delivereddoses: 18 μg per actuation of GP, and 0.5, 1.0, 3.6 or 4.8 μg peractuation of FF. The compositions and MDIs providing 0.5 μg FF and 1 μgFF per actuation are referred to as “ultra low” dose.

The drug specific aerodynamic size distributions achieved with MDIscontaining the co-suspension compositions prepared according to thisExample were determined as described in Example 1. The proportionalityof the aerodynamic size distributions of GP obtained from the low andhigh dose dual co-suspensions as well as the equivalency between thedual and monotherapy co-suspensions is demonstrated in FIG. 18. In thesame manner, the proportionality of the aerodynamic size distributionsof FF obtained from the dual and monotherapy co-suspensions, includingthe ultralow, low, and high dose compositions is demonstrated in FIG.19.

The delivered dose uniformity of the ultra low dose FF monotherapy MDIswas also measured as described in Example 1. The DDU for the 1μg/actuation and 0.5 μg/actuation compositions and systems are shown inFIG. 20. Desirable dose delivery uniformity is achieved even forultralow doses.

Example 12

The safety, efficacy and PK performance of combination co-suspensioncompositions as described herein delivered via a metered dose inhaler(MDI) were evaluated in a clinical trial. The combination co-suspensioncompositions contained both glycopyrrolate and formoterol fumarate. Theclinical trial was a randomized, double-blind, customized, unbalanced,incomplete block, crossover, multi-center study conducted in patientswith moderate to very severe Chronic Obstructive Pulmonary Disease(COPD). Two different combination co-suspension compositions asdescribed herein were compared to a placebo and four active comparatorcompositions delivering only one of the two active agents included inthe combination compositions.

The two combination co-suspension compositions administered in theclinical trial included both Glycopyrrolate (GP) and Formoterol Fumarate(FF) active agents delivered as a fixed combination. The combinationco-suspensions were prepared generally as described in Example 4, withthe GP and FF active agent particles provided as micronized, crystallineGP and FF material, the suspending particles being spray dried particlescomprising DSPC and CaCl₂, and the suspension medium being formed by HFA134a. The combination co-suspension compositions were prepared fordelivery to patients via an MDI as described herein and were tailored tofacilitate administration of two different doses of the GP and FF activeagents. The first co-suspension combination composition was formulatedto deliver 36 μg GP and 4.8 μg FF to a patient per actuation of the MDIand was used to dose 72 μg GP and 9.6 μg FF to patients twice daily (twoactuations of the MDI administered twice daily). This first compositionand treatment is also referred to in this example and the accompanyingfigures as “GP/FF 72/9.6” and the “GP/FF 72/9.6 treatment.” The secondco-suspension combination composition was formulated to deliver 18 μg GPand 4.8 μg FF to a patient per actuation of the MDI and was used to dose36 μg GP and 9.6 μg FF to patients twice daily (two actuations of theMDI administered twice daily). This second composition and treatment isalso referred to in this example and the accompanying figures as “GP/FF36/9.6” and the “GP/FF 36/9.6 treatment.”

The GP/FF 72/9.6 and GP/FF 36/9.6 treatments were compared against aplacebo and five different active compositions containing one of FF, GPor tiotropium as a single active agent. The first composition was anactive control, Spiriva Handihaler (tiotropium bromide inhalationpowder). Spiriva is a dry powder inhaler (DPI) product and wasadministered to patients once daily, with each DPI capsule including and18 μg dose of tiotropium. The next composition, Foradil Aerolizer(formoterol fumarate inhalation powder), was also an active control.Foradil is also a DPI product, but it was administered to patients twicedaily, and each DPI capsule included a 12 μg dose of FF. The thirdcomposition was a co-suspension composition including only GP as theactive agent. The monotherapy GP co-suspension composition (GP 36) wasmanufactured for pulmonary delivery via an MDI and was administeredtwice daily, with each administration delivering a 36 μg dose of GP tothe patient. The remaining two compositions were two differentmonotherapy co-suspension compositions including only FF as the activeingredient (FF 9.6 and FF 7.2). The monotherapy FF co-suspensioncompositions were manufactured for pulmonary delivery via an MDI andwere administered twice-daily, with each administration deliveringeither a 9.6 μg dose of FF (FF 9.6) or a 7.2 μg dose of FF (FF 7.2) tothe patient. The GP and FF monotherapy co-suspension compositions wereformulated using micronized, crystalline GP or FF material as activeagent particles, spray dried particles comprising DSPC and CaCl₂ as thesuspending particles, and HFA 134a as the suspension medium.

118 patients were randomized into the study and administered studycompositions over 7 day periods. On Day 7 of treatment, improvement inFEV₁ was assessed in each patient over a period of 12 hours postadministration of each of the study compositions, and the area under thecurve of the improvement in FEV₁ relative to baseline provided by eachof the study compositions over the twelve-hour period (AUC₀₋₁₂) wascalculated. The AUC₀₋₁₂ on treatment day 7 (Day 7) was used as theprimary endpoint for the study. Secondary endpoints included the peakchange in FEV₁ post administration of each of the study compositions(Peak FEV₁) on Day 1 and Day 7, the trough FEV₁ experienced by patientsafter chronic dosing for 7 days but prior to dosing on treatment Day 7(Morning Trough FEV₁) and safety assessments. The two GP/FFco-suspension compositions were safe and well-tolerated.

The percentage of subjects experiencing an improvement in FEV₁ of ≥12%from baseline on treatment day 1 (Day 1) and the rate at which suchimprovement was experienced is represented in FIG. 21. As can be seen inFIG. 21, the cumulative response and rate of onset provided by the GP/FF72/9.6 and GP/FF 36/9.6 treatments was greater than the cumulativeresponse and rate of onset provided by Spiriva. Relative to thecomparator compositions having only a single active agent, the GP/FF72/9.6 and GP/FF 36/9.6 treatments provided greater changes frombaseline in FEV₁ at Day 7 (shown in FIG. 22-FIG. 24).

Both GP/FF 72/9.6 and GP/FF 36/9.6 were superior to all the comparatorsfor the primary endpoint. FIG. 25 shows the improvement in FEV₁ AUC₀₋₁₂on Day 7 achieved by GP/FF 72/9.6, GP/FF 36/9.6, and each of the activecomparators relative to placebo. As is shown in FIG. 25, GP/FF 72/9.6and GP/FF 36/9.6 provided markedly better improvement in FEV₁ AUC₀₋₁₂ onDay 7 relative to the comparator compositions, with the improvement inFEV₁ AUC₀₋₁₂ on Day 7 provided by GP/FF 72/9.6 and GP/FF 36/9.6 being atleast 80 ml greater than that provided by each of the comparatorcompositions. The difference in FEV₁ AUC₀₋₁₂ on Day 7 shown in FIG. 26further highlights, for example, the improvement in FEV₁ AUC₀₋₁₂ on Day7 provided by the GP/FF 36/9.6 composition relative to the GP 36, FF9.6, Spiriva, and Foradil comparators.

Using the improvement in FEV₁ AUC₀₋₁₂ provided by the GP/FF 72/9.6treatment as a reference point, FIG. 32 presents the percent improvementin FEV₁ AUC₀₋₁₂ on Day 7 provided by GP/FF 36/9.6 and each of thecomparators in all patients, patients with moderate COPD, and patientswith severe to very severe COPD. The results shown in FIG. 32 illustratethat the response in patients was consistent regardless of the severityof COPD.

GP/FF 72/9.6 and GP/FF 36/9.6 were also superior to all othercomparators for the secondary endpoints of the study. The Peak FEV₁shown in FIG. 27 represents a change from baseline provided by each ofthe active study compositions relative to placebo on Day 1 and Day 7 ofadministration. As shown in FIG. 27, GP/FF 72/9.6 and GP/FF 36/9.6provided superior Peak FEV₁ on both Day 1 and Day 7. FIG. 28 highlightsthe improvement in Peak FEV₁ relative to Spiriva and Foradil provided byGP/FF 72/9.6 and GP/FF 36/9.6 on Day 1 and Day 7. FIG. 29 illustratesthe improvement in Morning Trough FEV₁ provided by GP/FF 72/9.6, GP/FF36/9.6, and each of the active comparators relative to placebo. As canbe appreciated by reference to FIG. 29, superior increases in FEV₁provided by the two combination co-suspensions are better maintainedover time, with the GP/FF 72/9.6 and GP/FF 36/9.6 compositions providingan approximately 50% improvement in Morning Trough FEV₁ relative to theother active comparators.

FIG. 30 shows the difference between the increase in pre-dose FEV₁ onDay 7 provided by GP/FF 72/9.6 and GP/FF 36/9.6 and the increase inpre-dose FEV₁ on Day 7 provided by the GP 36, FF 9.6, Spiriva andForadil comparators. As can be easily appreciated by reference to FIG.30, relative to the GP 36, FF 9.6, Spiriva and Foradil comparators, theGP/FF 36/9.6 treatment provided significantly greater improvements inpre-dose FEV₁ on Day 7.

In addition to the specified secondary endpoints for the study,improvements in inspiratory capacity (IC) were assessed. Both GP/FF72/9.6, GP/FF 36/9.6 provided greater increases in IC relative to eachof the comparators at Day 1 and on Day 7. For patients receiving GP/FF72/9.6, GP/FF 36/9.6, and Spiriva, FIG. 31 illustrates the peakimprovement in IC experienced on Day 1 (Day 1 Peak), the improvement inIC retained in patients prior to administration of the specified testcompositions on Day 7 (Day 7 Pre), and the peak improvement in ICexperienced in patients on Day 7 after administration of the specifiedcompositions (Day 7 Peak).

1.-61. (canceled)
 62. A pharmaceutical composition deliverable from ametered dose inhaler, comprising: a pharmaceutically acceptablepropellant; a first species of respirable active agent particlescomprising glycopyrrolate, or a pharmaceutically acceptable saltthereof; a second species of respirable active agent particlescomprising formoterol, or a pharmaceutically acceptable salt thereof; athird species of respirable active agent particles comprisingbudesonide, or a pharmaceutically acceptable salt thereof; wherein theglycopyrrolate, formoterol and budesonide, or pharmaceuticallyacceptable salts thereof, are included in the composition in aconcentration of between about 0.05 mg/mL and about 5 mg/mL; a pluralityof respirable suspending particles comprising1,2-distearoyl-sn-glycero-3-phosphocholine and calcium chloride in aconcentration of between about 3 mg/mL and about 10 mg/mL; and whereinthe pharmaceutical composition provides a clinically significantincrease in forced expiratory volume (FEV₁) upon administration to asubject in need thereof.
 63. The pharmaceutical composition of claim 62,wherein the glycopyrrolate, or a pharmaceutically acceptable saltthereof is present in a concentration of between about 0.04 mg/L andabout 2.25 mg/mL.
 64. The pharmaceutical composition of claim 62,wherein the glycopyrrolate, or a pharmaceutically acceptable saltthereof, is present in a concentration sufficient to provide a delivereddose of up to 10 μg upon actuation of the metered dose inhaler.
 65. Thepharmaceutical composition of claim 62, wherein the pharmaceuticallyacceptable salt of glycopyrrolate is3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidiniumbromide.
 66. The pharmaceutical composition of claim 62, wherein theformoterol, or a pharmaceutically acceptable salt thereof, is present ina concentration of between about 0.01 mg/mL and about 0.5 mg/mL.
 67. Thepharmaceutical composition of claim 62, wherein the formoterol, or apharmaceutically acceptable salt thereof, is present in a concentrationof between about 0.03 mg/L and about 0.04 mg/mL.
 68. The pharmaceuticalcomposition of claim 62, wherein the formoterol, or a pharmaceuticallyacceptable salt thereof, is present in a concentration sufficient toprovide a delivered dose of between about 1 μg and about 10 μg peractuation of the metered dose inhaler.
 69. The pharmaceuticalcomposition of claim 62, wherein the formoterol, is present in aconcentration sufficient to provide a delivered dose of between about 2μg and about 5 μg per actuation of the metered dose inhaler.
 70. Thepharmaceutical composition of claim 62, wherein the formoterol ispresent in a concentration sufficient to provide a delivered dose of upto 5 μg per actuation of the metered dose inhaler.
 71. Thepharmaceutical composition of claim 62, wherein the pharmaceuticallyacceptable salt of formoterol is formoterol fumarate.
 72. Thepharmaceutical composition of claim 71, wherein the formoterol fumarateis formoterol fumarate dihydrate.
 73. The pharmaceutical composition ofclaim 62, wherein the budesonide, or a pharmaceutically acceptable saltthereof, is present in a concentration sufficient to provide a delivereddose of between about 30 μg and about 240 μg.
 74. The pharmaceuticalcomposition of claim 62, wherein the budesonide, or a pharmaceuticallyacceptable sat thereof, is present in a concentration sufficient toprovide a delivered dose of up to about 240 μg.
 75. The pharmaceuticalcomposition of claim 62, wherein the respirable suspending particles arepresent in the composition in a concentration of between about 5 mg/mLand about 8 mg/mL.
 76. The pharmaceutical composition of claim 62,wherein the respirable suspending particles are present in thecomposition in a concentration of about 6 mg/mL.
 77. The pharmaceuticalcomposition of claim 62, wherein the clinically significant increase inforced expiratory volume (FEV₁) upon administration to a subject isabout 100 mL.
 78. The pharmaceutical composition of claim 62, whereinthe clinically significant increase in forced expiratory volume (FEV₁)upon administration is greater than 100 mL.